Showing papers in "Cardiovascular Research in 2007"
TL;DR: This review summarizes the current knowledge on the role of TGF-β in infarct healing and cardiac remodeling and suggests that T GF-β signaling may be crucial for repression of inflammatory gene synthesis in healing infarCTs mediating resolution of the inflammatory infiltrate.
Abstract: Transforming Growth Factor (TGF)-beta is markedly induced and rapidly activated in the infarcted myocardium. However, understanding of the exact role of TGF-beta signaling in the infarcted and remodeling heart has been hampered by the complex and unusual biology of TGF-beta activation and by the diversity of its effects eliciting multiple, and often opposing cellular responses. Experimental studies suggest that TGF-beta signaling may be crucial for repression of inflammatory gene synthesis in healing infarcts mediating resolution of the inflammatory infiltrate. In addition, TGF-beta may play an important role in modulating fibroblast phenotype and gene expression, promoting extracellular matrix deposition in the infarct by upregulating collagen and fibronectin synthesis and by decreasing matrix degradation through induction of protease inhibitors. TGF-beta is also a key mediator in the pathogenesis of hypertrophic and dilative ventricular remodeling by stimulating cardiomyocyte growth and by inducing interstitial fibrosis. In this review we summarize the current knowledge on the role of TGF-beta in infarct healing and cardiac remodeling.
818 citations
TL;DR: The overall health benefit of flavonoids is uncertain, and consumption of large quantities of them in fortified foods or supplements should not yet be encouraged.
Abstract: Flavonoids and other polyphenolic compounds have powerful antioxidant effects in vitro in many test systems, but can act as pro-oxidants in some others. Whether pro-oxidant, antioxidant, or any of the many other biological effects potentially exerted by flavonoids account for or contribute to the health benefits of diets rich in plant-derived foods and beverages is uncertain. Phenolic compounds may help to protect the gastrointestinal tract against damage by reactive species present in foods or generated within the stomach and intestines. The overall health benefit of flavonoids is uncertain, and consumption of large quantities of them in fortified foods or supplements should not yet be encouraged.
504 citations
TL;DR: A better knowledge of the intracellular signals of TGF-β can provide novel therapeutic approaches for fibrotic diseases, and blockers of AngII have demonstrated beneficial effects on many cardiovascular diseases and are now one of the best options to block T GF-β fibrotics responses.
Abstract: Transforming growth factor-β (TGF-β) participates in the pathogenesis of multiple cardiovascular diseases, including hypertension, restenosis, atherosclerosis, cardiac hypertrophy and heart failure. TGF-β exerts pleiotropic effects on cardiovascular cells, regulating cell growth, fibrosis and inflammation. TGF-β has long been believed to be the most important extracellular matrix regulator. We review the complex mechanisms involved in TGF-β-mediated vascular fibrosis that includes the Smad signaling pathway, activation of protein kinases and crosstalk between these pathways. TGF-β blockade diminishes fibrosis in experimental models, however better antifibrotic targets are needed for an effective therapy in human fibrotic diseases. A good candidate is connective tissue growth factor (CTGF), a downstream mediator of TGF-β-induced fibrosis. Among the different factors involved in vascular fibrosis, Angiotensin II (AngII) has special interest. AngII can activate the Smad pathway independent of TGF-β and shares with TGF-β many intracellular signals implicated in fibrosis. Blockers of AngII have demonstrated beneficial effects on many cardiovascular diseases and are now one of the best options to block TGF-β fibrotic responses. A better knowledge of the intracellular signals of TGF-β can provide novel therapeutic approaches for fibrotic diseases.
457 citations
TL;DR: The changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed and may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists.
Abstract: Endothelin (ET)-1 is a potent vasoconstrictor peptide originally isolated from endothelial cells. Its production is stimulated in a variety of different cell types under the influence of risk factors for cardiovascular disease and during the development of cardiovascular disease. Based on these observations and the biological effects induced by ET-1, including profound vasoconstriction, pro-inflammatory actions, mitogenic and proliferative effects, stimulation of free radical formation and platelet activation, ET-1 has been implicated as an important factor in the development of vascular dysfunction and cardiovascular disease. In the following the pathogenic role of ET-1, the mechanisms underlying the involvement of ET-1 for the development of vascular dysfunction and the potentially beneficial therapeutic effects of selective ETA and dual ETA/ETB receptor antagonists will be discussed. In particular the changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed. These changes may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists.
445 citations
TL;DR: Novel findings and critical appraisal regarding antioxidants, dietary fibers, omega-3 polyunsaturated fatty acids (n-3 PUFAs), nutraceuticals, vitamins, and minerals, are presented here in support of the current dietary habits together with physical exercise recommendations for prevention and treatment of CVD.
Abstract: Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease (CVD), one of the leading causes of morbidity and mortality worldwide. Physical inactivity and unhealthy eating contribute to these conditions. This article assesses the scientific rationale of benefits of physical activity and good nutrition on CVD, especially on atherosclerosis-related diseases. Compelling evidence has accumulated on the role of oxidative stress in endothelial dysfunction and in the pathogenesis of CVD. Reduced nitric oxide (NO) bioavailability due to oxidative stress seems to be the common molecular disorder comprising stable atherosclerotic narrowing lesions. Energy expenditure of about 1000 kcal (4200 kJ) per week (equivalent to walking 1 h 5 days a week) is associated with significant health benefits. Such benefits can be achieved through structured or nonstructured physical activity, accumulated throughout the day (even through short 10-min bouts) on most days of the week. Some prospective studies showed a direct inverse association between fruit and vegetable intake and the development of CVD incidents such as acute plaque rupture causing unstable angina or myocardial infarction and stroke. Many nutrients and phytochemicals in fruits and vegetables, including fiber, potassium, and folate, could be independently or jointly responsible for the apparent reduction in CVD risk. Novel findings and critical appraisal regarding antioxidants, dietary fibers, omega-3 polyunsaturated fatty acids (n-3 PUFAs), nutraceuticals, vitamins, and minerals, are presented here in support of the current dietary habits together with physical exercise recommendations for prevention and treatment of CVD.
426 citations
TL;DR: CeO2 nanoparticles protect against the progression of cardiac dysfunction and remodeling by attenuation of myocardial oxidative stress, ER stress, and inflammatory processes probably through their autoregenerative antioxidant properties.
Abstract: Objective: Cerium oxide (CeO2) nanoparticles have been shown to protect cells in culture from lethal stress, but no protection in vivo has been reported. Cardiac-specific expression of monocyte chemoattractant protein (MCP)-1 in mice causes ischemic cardiomyopathy associated with activation of endoplasmic reticulum (ER) stress. The aim of this study was to assess the effects of CeO2 nanoparticles on cardiac function and remodeling as well as ER stress response in this murine model of cardiomyopathy.
Methods: MCP-1 transgenic mice (MCP mice) and wild-type controls were administered intravenously 15 nmol of CeO2 nanoparticles or vehicle only twice a week for 2 weeks. Cardiac function, myocardial histology, nitrotyrosine formation, expression of cytokines, and ER stress-associated genes were evaluated.
Results: Treatment with CeO2 nanoparticles markedly inhibited progressive left ventricular dysfunction and dilatation in MCP mice and caused a significant decrease in serum levels of MCP-1, C-reactive protein, and total nitrated proteins. The infiltration of monocytes/macrophages, accumulation of 3-nitrotyrosine, apoptotic cell death, and expression of proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the myocardium were markedly inhibited by CeO2 nanoparticles. Expression of the key ER stress-associated genes, including glucose-regulated protein 78 (Grp78), protein disulfide isomerase (PDI), and heat shock proteins (HSP25, HSP40, HSP70), were also suppressed by CeO2 nanoparticles.
Conclusions: CeO2 nanoparticles protect against the progression of cardiac dysfunction and remodeling by attenuation of myocardial oxidative stress, ER stress, and inflammatory processes probably through their autoregenerative antioxidant properties.
414 citations
TL;DR: This review will focus on the biochemical partners and perturbations of the eNOS protein as this vital enzyme undergoes modulation by diverse signal transduction pathways in the vascular endothelium.
Abstract: The complex regulation of eNOS (endothelial nitric oxide synthase) in cardiovascular physiology occurs at multiple stages. eNOS mRNA levels are controlled both at the transcriptional and post-transcriptional phases, and epigenetic mechanisms appear to modulate tissue-specific eNOS expression. The eNOS enzyme reversibly associates with a diverse family of protein partners that regulate eNOS sub-cellular localization, catalytic function, and biological activity. eNOS enzyme activity and sub-cellular localization are intimately controlled by post-translational modifications including phosphorylation, nitrosylation, and acylation. The multiple extra-cellular stimuli affecting eNOS function coordinate their efforts through these key modifications to dynamically control eNOS and NO bioactivity in the vessel wall. This review will focus on the biochemical partners and perturbations of the eNOS protein as this vital enzyme undergoes modulation by diverse signal transduction pathways in the vascular endothelium.
397 citations
TL;DR: The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model that induces mature vessels and improves cardiac function more than each factor singly and may indicate clinical utility.
Abstract: Objective: This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate ...
388 citations
TL;DR: The role of mitochondria in the control of cell death in cardiac myocytes is discussed, including the release of factors such as cytochrome c, Smac, Omi/Htr2A, and AIF from mitochondria serves to activate a highly complex and regulated cell death program.
Abstract: Mitochondria are important generators of energy, providing ATP through oxidative phosphorylation. However, mitochondria also monitor complex information from the environment and intracellular milieu, including the presence or absence of growth factors, oxygen, reactive oxygen species, and DNA damage. Mitochondria have been implicated in the loss of cells in various cardiac pathologies, including ischaemia/reperfusion injury, cardiomyopathy, and congestive heart failure. The release of factors such as cytochrome c, Smac, Omi/Htr2A, and AIF from mitochondria serves to activate a highly complex and regulated cell death program. Furthermore, mitochondrial calcium overload might trigger opening of the mitochondrial permeability transition pore, causing uncoupling of oxidative phosphorylation, swelling of the mitochondria due to influx of water, and rupture of the mitochondrial outer membrane. In this review, we discuss the role of mitochondria in the control of cell death in cardiac myocytes.
382 citations
TL;DR: It appears that the basic mechanisms of cellular activation and migration in vascular inflammation are highly conserved across a variety of cardiovascular disease states and that major inflammatory events begin in the adventitia.
Abstract: Traditional concepts of vascular inflammation are considered "inside-out" responses centered on the monocyte adhesion and lipid oxidation hypotheses. These mechanisms likely operate in concert, holding the central tenet that the inflammatory response is initiated at the luminal surface. However, growing evidence supports a new paradigm of an "outside-in" hypothesis, in which vascular inflammation is initiated in the adventitia and progresses inward toward the intima. Hallmarks of the outside-in hypothesis include population of the adventitia with exogenous cell types, including monocytes, macrophages, and lymphocytes, the phenotypic switch of adventitial fibroblasts into migratory myofibroblasts, and increased vasa vasorum neovascularization. The resident and migrating cells deposit collagen and matrix components, respond to and upregulate inflammatory chemokines and/or antigens, and regulate the local redox state of the adventitia. B cells and T cells generate local humoral immune responses against local antigen presentation by foam cells and antigen presenting cells. These events result in increased local expression of cytokines and growth factors, evoking an inflammatory response that propagates inward toward the intima. Ultimately, it appears that the basic mechanisms of cellular activation and migration in vascular inflammation are highly conserved across a variety of cardiovascular disease states and that major inflammatory events begin in the adventitia.
371 citations
TL;DR: A novel proangiogenic role of H(2)S which is dependent on activation of Akt is reported which is able to promote angiogenesis in vivo in mice.
Abstract: Objective Hydrogen sulfide (H2S) has been reported to be a gasotransmitter which regulates cardiovascular homeostasis. The present study aims to examine the hypothesis that hydrogen sulfide is able to promote angiogenesis.
Methods Angiogenesis was assessed using in vitro parameters ( i.e. endothelial cell proliferation, adhesion, transwell migration assay, scratched wound healing and formation of tube-like structure) and in vivo by assessing neovascularization in mice. Phosphorylation of Akt was measured using Western blot analysis.
Results Exogenously administered NaHS (H2S donor) concentration-dependently (10–20 μmol/l) increased cell growth, migration, scratched wound healing and tube-like structure formation in cultured endothelial cells. These effects of NaHS on endothelial wound healing and tube-like structure formation were prevented by either the phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002 (5 μmol/l) or transfection of a dominant-negative mutant of Akt. NaHS increased Akt phosphorylation and this effect was also blocked by either LY 294002 or wortmannin (25 nmol/l). NaHS did not significantly alter the levels of vascular endothelial growth factor, mRNA expression of fibroblast growth factor and angiopoietin-1, or nitric oxide metabolites. NaHS treatment (10 and 50 μmol kg−1 day−1) significantly promoted neovascularization in vivo in mice.
Conclusion The present study reports a novel proangiogenic role of H2S which is dependent on activation of Akt.
TL;DR: The aim of this article is to carefully review the importance of CD36 as an essential component in the pathogenesis of atherosclerosis.
Abstract: CD36 is a multi-ligand scavenger receptor present on the surface of a number of cells such as platelets, monocytes/macrophages, endothelial and smooth muscle cells. Monocyte/macrophage CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and endocytose oxidized low density lipoproteins (OxLDL), and it is implicated in the formation of foam cells. However, the significance of CD36 in atherosclerosis has recently been called into question by different studies, and therefore its exact role still needs to be clarified. The aim of this article is to carefully review the importance of CD36 as an essential component in the pathogenesis of atherosclerosis.
TL;DR: The omega-3 index is a new risk factor to be considered for sudden cardiac death, measured in red blood cells, and is expressed as a percentage of EPA + DHA of total fatty acids.
Abstract: Cardiac societies recommend the intake of 1 g/day of the two omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for cardiovascular disease prevention, treatment after a myocardial infarction, prevention of sudden death, and secondary prevention of cardiovascular disease. These recommendations are based on a body of scientific evidence that encompasses literally thousands of publications. Of four large scale intervention studies three also support the recommendations of these cardiac societies. One methodologically questionable study with a negative result led a Cochrane meta-analysis to a null conclusion. This null conclusion, however, has not swayed the recommendations of the cardiac societies mentioned, and has been refuted with good reason by scientific societies. Based on the scientific evidence just mentioned, we propose a new risk factor to be considered for sudden cardiac death, the omega-3 index. It is measured in red blood cells, and is expressed as a percentage of EPA + DHA of total fatty acids. An omega-3 index of >8% is associated with 90% less risk for sudden cardiac death, as compared to an omega-3 index of 8%).
TL;DR: The epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases will be discussed, including its role in the setting of pathological cardiac remodeling and acute cardiac injury.
Abstract: Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5' AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss the epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.
TL;DR: Important aspects of the role of CaMKII in ECC are summarized with an emphasis on recent novel findings.
Abstract: Calcium (Ca2+) is the central second messenger in the translation of electrical signals into mechanical activity of the heart. This highly coordinated process, termed excitation–contraction coupling or ECC, is based on Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR). In recent years it has become increasingly clear that several Ca2+-dependent proteins contribute to the fine tuning of ECC. One of these is the Ca2+/calmodulin-dependent protein kinase (CaMK) of which CaMKII is the predominant cardiac isoform. During ECC CaMKII phosphorylates several Ca2+ handling proteins with multiple functional consequences. CaMKII may also be co-localized to distinct target proteins. CaMKII expression as well as activity are reported to be increased in heart failure and CaMKII overexpression can exert distinct and novel effects on ECC in the heart and in isolated myocytes of animals. In the present review we summarize important aspects of the role of CaMKII in ECC with an emphasis on recent novel findings.
TL;DR: In this paper, a review outlines the known interaction partners of titin, highlights the putative stress/stretch-sensor complexes at titin's NH(2) and COOH termini and their role in myopathies, and summarizes the known disease-associated mutations in those titin regions.
Abstract: Mechanical stress signals transmitted through the heart walls during hemodynamic loading are sensed by the myocytes, which respond with changes in contractile performance and gene expression. External forces play an important role in physiological heart development and hypertrophy, but disruption of the well-balanced stress-sensing machinery causes mechanical dysregulation, cardiac remodelling, and heart failure. Nodal points of mechanosensing in the cardiomyocytes may reside in the Z-disk, I-band, and M-band regions of the sarcomeres. Longitudinal linkage of these regions is provided by the titin filament, and several 'hot spots' along this giant protein, in complex with some of its >20 ligands, may be pivotal to the myofibrillar stress or stretch response. This review outlines the known interaction partners of titin, highlights the putative stress/stretch-sensor complexes at titin's NH(2) and COOH termini and their role in myopathies, and summarizes the known disease-associated mutations in those titin regions. Another focus is the elastic I-band titin section, which interacts with a diverse number of proteins and whose main function is as a determinant of diastolic distensibility and passive stiffness. The discussion centers on recent insights into the plasticity, mechanical role, and regulation of the elastic titin springs during cardiac development and in human heart disease. Titin and titin-based protein complexes are now recognized as integral parts of the mechanosensitive protein network and as critical components in cardiomyocyte stress/stretch signalling.
TL;DR: It is concluded that PC with the chemokine SDF-1 suppresses MSCs apoptosis, enhances their survival, engraftment, and vascular density, and improves myocardial function via SDF/CXCR4 signaling.
Abstract: Aims We hypothesized that preconditioning (PC) with stromal-derived factor 1 alpha (SDF-1) significantly enhances cell survival, proliferation, and engraftment of bone marrow-derived mesenchymal stem cells (MSCs) via SDF-1/CXCR4 signaling.
Methods and results MSCs were cultured and then incubated in medium for 60 min without SDF-1 (control group) or with SDF-1 0.05 µg/mL (SDF-1 group) or CXCR4-selective antagonist, AMD 3100 (AMD) (5 µg/mL, AMD group) or SDF-1 and AMD (0.05 µg/mL, 5 µg/mL, respectively, SDF-1+AMD group). MSCs were treated for 60 min, washed in normal medium, and then exposed to H2O2 (100 µmol/L) for 60 min to determine the effects of various treatments on cell injury, viability, and proliferation. For in vivo studies, rats were grouped ( n = 6) after left anterior descending coronary artery ligation to receive 20 µL Dulbecco’s modified Eagle’s medium without cells or with 5 × 105 non-preconditioned MSCs (control group), SDF-1 preconditioned MSCs (SDF-1 group), AMD (AMD group), or MSCs treated with SDF-1 plus AMD (SDF-1+AMD group). Heart function, infarct size, fibrosis, and MSC proliferation and differentiation in infarcted myocardium were determined after 4 weeks. In vitro data showed a marked increase in cell viability and proliferation following SDF-1 PC. In vivo data in preconditioned group showed a robust cell proliferation, reduction in infarct size and fibrosis, and significant improvement in cardiac function. Effects of SDF-1 PC were abrogated by CXCR4 antagonist.
Conclusion We conclude that PC with the chemokine SDF-1 suppresses MSCs apoptosis, enhances their survival, engraftment, and vascular density, and improves myocardial function via SDF/CXCR4 signaling. Chemokine PC is a novel approach for enhancing stem cell survival and regeneration of infarcted myocardium.
TL;DR: Nitration of tyrosine can affect protein function, which could directly link nitroxidative stress to the molecular alterations found in disease and pharmacological strategies directed towards inhibiting protein nitration will help shed light on the relevance of this post-translational modification to human cardiovascular pathology.
Abstract: Several pathologies of the cardiovascular system are associated with an augmented production of nitric oxide and/or superoxide-derived oxidants and/or alteration in the antioxidant detoxification pathways that lead to nitroxidative stress. One important consequence of these reactive intermediates at the biochemical level is the nitration of protein tyrosines, which is performed through either of two of the relevant nitration pathways that operate in vivo, namely peroxynitrite and heme peroxidase-dependent nitration. Proteins nitrated at tyrosine residues have been detected in several compartments of the cardiovascular system. In this review a selection of nitrated proteins in plasma (fibrinogen, plasmin, Apo-1), vessel wall (Apo-B, cyclooxygenase, prostaglandin synthase, Mn-superoxide dismutase) and myocardium (myofibrillar creatine kinase, α-actinin, sarcoplasmic reticulum Ca 2+ ATPase) are analyzed in the context of cardiovascular disease. Nitration of tyrosine can affect protein function, which could directly link nitroxidative stress to the molecular alterations found in disease. While some proteins are inactivated by nitration (e.g. Mn-SOD) others undergo a gain-of-function (e.g. fibrinogen) that can have an ample impact on the pathophysiology of the cardiovascular system. Nitrotyrosine is also emerging as a novel independent marker of cardiovascular disease. Pharmacological strategies directed towards inhibiting protein nitration will assist to shed light on the relevance of this post-translational modification to human cardiovascular pathology.
TL;DR: This study demonstrates that the mPTP plays a critical role in the cardioprotection elicited by ischemic and pharmacological preconditioning and postconditioning.
Abstract: Objective The opening of the mitochondrial permeability transition pore (mPTP) at the time of myocardial reperfusion is a critical determinant of cell death. Emerging studies suggest that suppression of mPTP opening may underlie the cardioprotection elicited by both ischemic preconditioning (IPC) and postconditioning (IPost). To further evaluate the role of the mPTP in cardioprotection, we hypothesized that hearts deficient in cyclophilin-D (CYP-D−/−), a key component of the mPTP, will be resistant to cardioprotection conferred by ischemic and pharmacological preconditioning and postconditioning.
Methods and results Male/female wild type or CYP-D−/− mice were subjected to 30 min of ischemia and 120 min of reperfusion. In wild type mice subjected to in vivo myocardial ischemia–reperfusion injury, a significant reduction in myocardial infarct size was observed with the following treatments ( n ≥6/group; P 0.05).
Conclusion This study demonstrates that the mPTP plays a critical role in the cardioprotection elicited by ischemic and pharmacological preconditioning and postconditioning.
TL;DR: The complex interplay of hormonal systems in energy balance in patients with chronic heart failure as well as other factors such as malabsorption and dietary deficiencies that contribute to the wasting process are described.
Abstract: Chronic heart failure is a complex catabolic state that carries a devastating prognosis. The transition from stable disease to cardiac cachexia is not well understood. Mechanisms that maintain the wasting process involve neurohormones and pro-inflammatory cytokines, which contribute to an imbalance in anabolic and catabolic pathways. A decrease in food intake alone rarely triggers the development of a wasting process, but dietary deficiencies in micronutrients and macronutrients contribute to the progression of the disease. Malabsorption from the gut as a result of bowel wall edema and decreased bowel perfusion also plays an important role. This article describes the complex interplay of hormonal systems in energy balance in patients with chronic heart failure as well as other factors such as malabsorption and dietary deficiencies that contribute to the wasting process. Finally, therapeutic approaches are discussed. These include dietary advice, ongoing studies, and future possibilities.
TL;DR: Phagocytosis is a crucial process involved in atherogenesis that may significantly affect the stability of the atherosclerotic plaque and several lines of evidence indicate that autophagy is initiated in plaque smooth muscle cells as a result of cellular distress.
Abstract: Macrophages play a key role in atherosclerotic plaque destabilization and rupture. In this light, selective removal of macrophages may be beneficial for plaque stability. However, macrophages are phagocytic cells and thus have an important additional role in scavenging of modified lipoproteins, unwanted or dead cells and cellular debris via phagocytosis. The concept of phagocytosis as well as the underlying mechanisms is well defined but the effect of phagocytosis in terms of plaque stability remains poorly understood. Recent findings point towards a complex role of macrophage phagocytosis in atherogenesis. Macrophages are necessary for removal of apoptotic cells from plaques, but exert strong proatherogenic properties upon phagocytosis of lipoproteins, erythrocytes and platelets. Apart from heterophagy, autophagocytosis better known as autophagy may occur in advanced atherosclerotic plaques. Several lines of evidence indicate that autophagy is initiated in plaque smooth muscle cells as a result of cellular distress. Since autophagy is well recognized as a survival mechanism, autophagic smooth muscle cells in the fibrous cap may reflect an important feature underlying plaque stability. All together, phagocytosis is a crucial process involved in atherogenesis that may significantly affect the stability of the atherosclerotic plaque.
TL;DR: This review critically evaluates the evidence supporting TGFbeta as a pro-fibrotic cytokine, with special attention to cardiac fibrosis, and suggests several possible points for selective drug intervention to combat chronic fibrotic disease.
Abstract: The cytokine transforming growth factor beta (TGFbeta) is a major contributor to fibrogenic responses both in vitro and in vivo. TGFbeta possesses many functions; thus, broadly targeting TGFbeta signaling as an anti-fibrotic approach is anticipated to be problematic. Recent experiments, however, have begun to elucidate the signaling pathways through which TGFbeta activates a fibrotic program. This review critically evaluates the evidence supporting TGFbeta as a pro-fibrotic cytokine, with special attention to cardiac fibrosis, and suggests several possible points for selective drug intervention to combat chronic fibrotic disease.
TL;DR: It turns out that the merits of currently used drugs--ACE inhibitors, AT1R blockers and mineralocorticoid receptor blockers - lay beyond their direct effects on suppression of the ACE-Ang II-AT1R axis as they also increase cardiac ACE2 and Ang (1-7) significantly.
Abstract: Angiotensin II (Ang II), a bioactive peptide of the renin-angiotensin system (RAAS), plays an important role in the development of cardiovascular diseases (CVD). Pharmacological inhibition of angiotensin-converting enzyme (ACE), the Ang II forming enzyme, or specific blockade of Ang II binding to angiotensin type 1 receptor (AT1R) through which it exerts its deleterious effects, were shown to provide some protection against progression of CVD. The ACE-Ang II-AT1R axis has been challenged over the last few years with RAAS components able to counterbalance the effects of the main axis. The ACE homologue ACE2 efficiently hydrolyses Ang II to form Ang (1-7), a peptide that exerts actions opposite to those of Ang II. In contrast to the Ang II axis, the role of the ACE2-Ang (1-7) axis in cardiac function is largely obscure. Ang (1-7) is present in the viable myocardium, and its formation depends on Ang II as a substrate. The expression of this peptide is associated with cardiac remodeling: it is lost in the infarcted area and significantly increased in the border area. Low doses of Ang (1-7) improve cardiac output and antagonize Ang II-induced vasoconstriction. The type of Ang (1-7) biological activity is tissue specific and dose dependent. These findings point to a possible protective role for Ang (1-7) in abating the Ang II-induced actions. The elevated expression of Ang (1-7) in failing heart tissue paralleled the expression of its forming enzyme, ACE2. Several observations and experimental evidence suggest a beneficial role for ACE2 in cardiovascular function. Elevated ACE2 expression at the initial stage of several pathologies which decline with progression of disease might indicate a protective role for ACE2. Genetic manipulation of ACE2 expression, either targeted disruption or overexpression, point to the possible significance of this enzyme in cardiac function. Based on the above, a therapeutic approach that will amplify the ACE2-Ang (1-7) axis could provide further protection against the development of CVD. It turns out that the merits of currently used drugs--ACE inhibitors, AT1R blockers and mineralocorticoid receptor blockers (MRB) - lay beyond their direct effects on suppression of the ACE-Ang II-AT1R axis as they also increase cardiac ACE2 and Ang (1-7) significantly.
TL;DR: Adiponectin is a novel humoral vasodilator that relaxes aortic and mesenteric rings by opening K(v) channels in rat arteries and plays a role in the paracrine control of vascular tone by perivascular adipose tissue.
Abstract: Objectives Perivascular adipose tissue secretes an adipocyte-derived relaxing factor(s) (ADRF) that opens Kv channels in rat arteries. Visceral fat accumulation causes adipocyte dysfunction, including hyposecretion of adiponectin. We tested the hypothesis that ADRF might be adiponectin and that adiponectin plays a role in the paracrine control of vascular tone by perivascular adipose tissue.
Methods and results We studied Sprague–Dawley rats, wild-type and adiponectin gene-deficient (Apn 1−/−) mice, and New Zealand obese (NZO) mice. In rat aortas, recombinant adiponectin at serum levels (2–5 μg/ml) inhibited serotonin-induced contractions. The effects were abolished by Kv channel inhibition with 4-aminopyridine (4-AP, 2 mM). Similar effects were observed in NZO mouse mesenteric arteries. To study vascular function in Apn 1−/− mice, the mesenteric vascular bed was isolated, cannulated, and perfused at a constant 4–5-ml/min flow in the absence and presence of serotonin. 4-AP (2 mM) induced a similar increase in perfusion pressure in the Apn 1−/− perfused isolated mesenteric vascular bed, compared to wild-type mice. Removal of perivascular fat increased the vasoconstrictor responses, but abolished the 4-AP effects. The anti-contractile effects of perivascular fat were similar in mesenteric artery and aortic rings from Apn 1−/− and wild-type mice. Despite high adiponectin levels, the anti-contractile effects of perivascular fat were diminished in mesenteric arteries of NZO mice with age.
Conclusion Adiponectin is a novel humoral vasodilator that relaxes aortic and mesenteric rings by opening Kv channels. Similar to the rat, perivascular adipose tissue of the mouse harbors an ADRF, which is malfunctional in NZO mice and is not adiponectin.
TL;DR: The cardiovascular phenotypes of each of the NO synthase (NOS) gene knockout mice, and the insights gained into the roles of NO in the cardiovascular system are discussed.
Abstract: Nitric oxide (NO) is a gaseous molecule that plays many key roles in the cardiovascular system. Each of the enzymes that generate NO—neuronal, inducible and endothelial NO synthase—has been genetically disrupted in mice. This review discusses the cardiovascular phenotypes of each of the NO synthase (NOS) gene knockout mice, and the insights gained into the roles of NO in the cardiovascular system. Mice lacking the endothelial isoform are hypertensive, have endothelial dysfunction and show a more severe outcome in response to vascular injury, to stroke and cerebral ischaemia, and to diet-induced atherosclerosis. Mice lacking the neuronal isoform show a less severe outcome in response to stroke and cerebral ischaemia but have increased diet-induced atherosclerosis. Mice lacking the inducible isoform show reduced hypotension to septic shock. Together, NOS gene knockout mice have been useful tools that complement our other approaches to studying the multiple roles of NO in the cardiovascular system.
TL;DR: HIF-1 alpha is required for IPC-induced mitochondrial ROS production and myocardial protection against ischaemia-reperfusion injury and is impaired in HET hearts.
Abstract: Aims We investigated whether hypoxia-inducible factor 1α (HIF-1α) plays a role in the acute phase of ischaemic preconditioning (IPC).
Methods and results Hearts from wild-type (WT) mice and mice heterozygous for a null allele at the locus encoding HIF-1α (HET) were subjected to IPC (10-min ischaemia/5 min reperfusion, or two cycles of 5 min ischaemia/5 min reperfusion), followed by 30 min ischaemia and reperfusion. Left ventricular-developed pressure, heart rate, and coronary flow rate were measured continuously. Apoptosis and infarct size were assessed by TUNEL assay, cleaved caspase 3 immunohistochemistry, and triphenyltetrazolium chloride staining. Production of reactive oxygen species (ROS) in isolated cardiac mitochondria was measured by a chemiluminescence assay. The phosphatase and tensin homologue (PTEN) and AKT (protein kinase B) were analysed by immunoblot assay. IPC improved functional recovery and limited infarct size and apoptosis after prolonged ischaemia–reperfusion in WT hearts, but not in HET hearts. Mitochondrial ROS production, PTEN oxidation, and AKT phosphorylation were impaired in HET hearts. WT and HET hearts were protected by adenosine, which acts via an ROS-independent mechanism.
Conclusion HIF-1α is required for IPC-induced mitochondrial ROS production and myocardial protection against ischaemia–reperfusion injury.
TL;DR: SerCA2a is a major regulator of intracellular Ca( 2+) homeostasis, and changes in the expression and activity of the SERCA pump contribute to the decreased SR Ca(2+) content and cardiac dysfunction during pathogenesis.
Abstract: Cardiac sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) plays a central role in myocardial contractility. SERCA2a actively transports Ca(2+) into the SR and regulates cytosolic Ca(2+) concentration, SR Ca(2+) load, and the rate of contraction and relaxation of the heart. In the heart, SERCA pump activity is regulated by two small molecular weight proteins: phospholamban (PLB) and sarcolipin (SLN). Decreases in the expression levels of SERCA2a have been observed in a variety of pathological conditions. In addition, altered expression of PLB and SLN has been reported in many cardiac diseases. Thus, SERCA2a is a major regulator of intracellular Ca(2+) homeostasis, and changes in the expression and activity of the SERCA pump contribute to the decreased SR Ca(2+) content and cardiac dysfunction during pathogenesis. In this review, we discuss the mechanisms controlling SERCA pump expression and activity both during normal physiology and under pathological states.
TL;DR: More detailed and profound analysis of molecular actions in different cells of the cardiovascular system is necessary before safe clinical use of tea polyphenols for treatment of cardiovascular diseases will become possible.
Abstract: Tea-derived polyphenols have attracted considerable attention in the prevention of cancer and cardiovascular diseases. In comparison to tumour cells, the elucidation of their molecular targets in cardiovascular relevant cells is still at the beginning. Although promising experimental and clinical data demonstrate protective effects for the cardiovascular system, little information is actually available on how these beneficial effects of tea polyphenols are mediated at the cellular level. By affecting the activity of receptor and signal transduction kinases, both catechins and theaflavins--the major ingredients of green and black tea, respectively--exert a variety of cardiovascular beneficial effects. In general, the number and positions of galloyl groups have major influence on the potency of polyphenols. Compared to their broad impact on cellular signal transduction, tea polyphenols reveal little transcriptional effects. However, more detailed and profound analysis of molecular actions in different cells of the cardiovascular system is necessary before safe clinical use of tea polyphenols for treatment of cardiovascular diseases will become possible.
TL;DR: This Review focuses on chronic angiogenic responses due to local cytokine accumulations such as occur in the wall of arteries in the presence of hypertension, hypercholesterolemia, accumulation of lipids, extravasated blood products which attract monocytes, and response of vasa vasorum to pharmacological stimuli.
Abstract: The function of vasa vasorum is both to deliver nutrients and oxygen to arterial and venous walls and to remove "waste" products, either produced by cells in the wall or introduced by diffusional transport through the endothelium of the artery or vein. Although the relationship between changes in vasa vasorum characteristics and the development of atheromatous plaques is well documented, the role of vasa vasorum, especially in terms of their appearance and disappearance in disease processes such as atherosclerosis, are still not clearly understood in terms of their being causative or merely reactive. However, even if their proliferation is merely reactive, these new microvessels may be a source of disease progression by virtue of endothelial impairment and as a pathway for monocytic cells to migrate to sites of early disease. As both these features are aspects of the vasa vasorum function, this Review focuses on the following issues: 1) acute modulation of vasa vasorum patency due to surrounding compressive forces within vessel wall and due to variable tone in the smooth muscle within proximal vasa vasorum and 2) chronic angiogenic responses due to local cytokine accumulations such as occur in the wall of arteries in the presence of hypertension, hypercholesterolemia, accumulation of lipids, extravasated blood products (e.g., red blood cells, macrophages, inflammatory products) which attract monocytes, and response of vasa vasorum to pharmacological stimuli.
TL;DR: It is demonstrated that the age-dependent cardiomyopathy in ACE2 null mice is related to increased Ang II-mediated oxidative stress and neutrophilic infiltration via AT1 receptors.
Abstract: Objectives The peptidase action of angiotensin converting enzyme 2 (ACE2) allows it to function as a negative regulator of the renin–angiotensin system. Current pharmacotherapies for human heart failure, such as ACE inhibitors and angiotensin and aldosterone receptor blockers, increase the activity of ACE2 in the heart. In this study, we investigate the mechanism for the age-dependent cardiomyopathy in ACE2 null mice.
Methods and results Ace2 −/y mutant mice develop a progressive age-dependent dilated cardiomyopathy with increased oxidative stress, neutrophilic infiltration, inflammatory cytokine and collagenase levels, mitogen-activated protein kinase (MAPK) activation and pathological hypertrophy. The angiotensin II receptor-1 (AT1) blocker, irbesartan, prevented the dilated cardiomyopathy in aged Ace2 −/y mutant mice, confirming a critical role of angiotensin II (Ang II)-mediated stimulation of AT1 receptors. Ang II activation of AT1 receptors triggers G-protein-coupled receptor (GPCR)-activated phosphoinositide 3-kinase gamma (PI3Kγ) and its downstream pathways. We showed that p110γ, the catalytic subunit of PI3Kγ, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice ( Ace2 −/y /p110γ −/− ) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3Kγ plays a critical role in Ang II-mediated cardiomyopathy.
Conclusions Our findings demonstrate that the age-dependent cardiomyopathy in ACE2 null mice is related to increased Ang II-mediated oxidative stress and neutrophilic infiltration via AT1 receptors. Our combination of genetic and pharmacological approaches defines a critical role of ACE2 in the suppression of Ang II-mediated heart failure.