Showing papers in "Journal of Cardiovascular Pharmacology in 2015"

Pharmacologic Inhibition of the NLRP3 Inflammasome Preserves Cardiac Function After Ischemic and Nonischemic Injury in the Mouse.

Abstract: Background Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage.

ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy.

Abstract: The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (Angiotensin-converting enzyme [ACE]/Angiotensin II [Ang II]/Ang II type 1 receptor [AT1R]) and vasoprotective (Angiotensin-converting enzyme 2 [ACE2]/Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor [MasR]) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1-7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. Although multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggest that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health.

At2 receptor activities and pathophysiological implications

Abstract: :Although angiotensin II subtype-2 receptor (AT2R) was discovered over 2 decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1

Oral L-carnitine supplementation increases trimethylamine-N-oxide but reduces markers of vascular injury in hemodialysis patients.

Abstract: Objectives:Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in acc

MicroRNA-133a engineered mesenchymal stem cells augment cardiac function and cell survival in the infarct heart.

Abstract: Cardiovascular disease is the number 1 cause of morbidity and mortality in the United States. The most common manifestation of cardiovascular disease is myocardial infarction (MI), which can ultimately lead to congestive heart failure. Cell therapy (cardiomyoplasty) is a new potential therapeutic treatment alternative for the damaged heart. Recent preclinical and clinical studies have shown that mesenchymal stem cells (MSCs) are a promising cell type for cardiomyoplasty applications. However, a major limitation is the poor survival rate of transplanted stem cells in the infarcted heart. miR-133a is an abundantly expressed microRNA (miRNA) in the cardiac muscle and is downregulated in patients with MI. We hypothesized that reprogramming MSCs using miRNA mimics (double-stranded oligonucleotides) will improve survival of stem cells in the damaged heart. MSCs were transfected with miR-133a mimic and antagomirs, and the levels of miR-133a were measured by quantitative real-time polymerase chain reaction. Rat hearts were subjected to MI and MSCs transfected with miR-133a mimic or antagomir were implanted in the ischemic hearts. Four weeks after MI, cardiac function, cardiac fibrosis, miR-133a levels, and apoptosis-related genes (Apaf-1, Caspase-9, and Caspase-3) were measured in the heart. We found that transfecting MSCs with miR-133a mimic improves survival of MSCs as determined by the MTT assay. Similarly, transplantation of miR-133a mimic transfected MSCs in rat hearts subjected to MI led to a significant increase in cell engraftment, cardiac function, and decreased fibrosis when compared with MSCs only or MI groups. At the molecular level, quantitative real-time polymerase chain reaction data demonstrated a significant decrease in expression of the proapoptotic genes; Apaf-1, caspase-9, and caspase-3 in the miR-133a mimic transplanted group. Furthermore, luciferase reporter assay confirmed that miR-133a is a direct target for Apaf-1. Overall, bioengineering of stem cells through miRNAs manipulation could potentially improve the therapeutic outcome of patients undergoing stem cell transplantation for MI.

MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells.

Abstract: Osteoblast differentiation of valve interstitial cells (VICs) is a key step in valve calcification, but the molecular mechanisms involved are not fully understood. In this study, we aimed to investigate whether microRNA (miR)-204-regulated VICs differentiation through modulation of runt-related transcription factor 2 (Runx2), a key transcription factor for osteogenesis. Our data demonstrated that miR-204 was markedly downregulated in both human calcified aortic valves and bone morphogenetic protein (BMP)-2-stimulated aortic VICs. In vitro experiments showed that miR-204 acted as a negative regulator of osteogenic differentiation by repressing Runx2 and thereby inhibiting expression of osteoblast-related genes, including alkaline phosphatase and osteocalcin, which were all induced by BMP-2. Luciferase reporter assays validated Runx2 as the direct target of miR-204. Furthermore, increased alkaline phosphatase activity and osteocalcin expression after miR-204 inhibition were abolished by small interfering RNA-mediated silencing of Runx2. Overall, these data suggested miR-204 as a possible molecular switch inhibiting osteoblastic transdifferentiation of human aortic VICs and targeting miR-204 may have therapeutic potential for human aortic valve calcification.

Oxidant and Inflammatory Mechanisms and Targeted Therapy in Atrial Fibrillation: An Update.

Abstract: Atrial fibrillation (AF) is an important cause of stroke and risk factor for heart failure and death. Current pharmacologic treatments for AF have limited efficacy, and treatments that more directly target the underlying causes of AF are needed. Oxidant stress and inflammatory activation are interrelated pathways that promote atrial electrical and structural remodeling, leading to atrial ectopy, interstitial fibrosis, and increased stroke risk. This review evaluates the impact of common stressors on atrial oxidant stress and inflammatory activation and the contribution of these pathways to atrial remodeling. Recent studies suggest that integrated efforts to target the underlying risk factors, rather than the AF per se, may have a greater impact on health and outcomes than isolated efforts focused on the electrical abnormalities.

Boldine Ameliorates Vascular Oxidative Stress and Endothelial Dysfunction: Therapeutic Implication for Hypertension and Diabetes.

Abstract: Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, are a rich source of antioxidants. Boldine [(S)-2,9-dihydroxy-1,10-dimethoxy-aporphine], an aporphine alkaloid, is a potent antioxidant found in the leaves and bark of the Chilean boldo tree. Boldine has been extensively reported as a potent "natural" antioxidant and possesses several health-promoting properties like anti-inflammatory, antitumor promoting, antidiabetic, and cytoprotective. Boldine exhibited significant endothelial protective effect in animal models of hypertension and diabetes mellitus. In isolated thoracic aorta of spontaneously hypertensive rats, streptozotocin-induced diabetic rats, and db/db mice, repeated treatment of boldine significantly improved the attenuated acetylcholine-induced endothelium-dependent relaxations. The endothelial protective role of boldine correlated with increased nitric oxide levels and reduction of vascular reactive oxygen species via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase subunits, p47 and nicotinamide adenine dinucleotide phosphate oxidase 2, and angiotensin II-induced bone morphogenetic protein-4 oxidative stress cascade with downregulation of angiotensin II type 1 receptor and bone morphogenetic protein-4 expression. Taken together, it seems that boldine may exert protective effects on the endothelium via several mechanisms, including protecting nitric oxide from degradation by reactive oxygen species as in oxidative stress-related diseases. The present review supports a complimentary therapeutic role of the phytochemical, boldine, against endothelial dysfunctions associated with hypertension and diabetes mellitus by interfering with the oxidative stress-mediated signaling pathway.

Cardioprotective effects of luteolin on ischemia/reperfusion injury in diabetic rats are modulated by eNOS and the mitochondrial permeability transition pathway.

Abstract: Myocardial ischemia/reperfusion (I/R) injury in diabetes is associated with oxidative stress, endothelial nitric oxide synthase (eNOS) dysfunction, and mitochondrial collapse, whereas luteolin is known to protect the cardiovascular system against diabetes and I/R injury. Here, we investigated whether luteolin pretreatment diminishes myocardial I/R injury in diabetic rats by affecting eNOS and the mitochondrial permeability transition pore (mPTP). After diabetic rats were produced by streptozotocin treatment (65 mg/kg) for 3 weeks, luteolin (100 mg·kg·d) or L-NAME (25 mg·kg·d) was administered intragastrically for 2 weeks. Hearts were then isolated and subjected to 30 minutes of global ischemia followed by 120 minutes of reperfusion. Pretreatment with luteolin significantly improved left ventricular function and coronary flow throughout reperfusion, increased cardiac tissue viability and manganese superoxide dismutase (MnSOD) activity, and reduced coronary lactate dehydrogenase release, and the myocardial malonaldehyde level in diabetic I/R rat hearts. All these improving effects of luteolin were significantly attenuated by L-NAME. Luteolin also significantly upregulated eNOS expression in diabetic rat hearts after I/R. Ca-induced mPTP opening and mitochondrial inner membrane potential reduction were significantly inhibited in ventricular myocytes isolated from luteolin-treated diabetic rats, and this effect was attenuated by L-NAME. These findings indicate that luteolin protects the diabetic heart against I/R injury by upregulating the myocardial eNOS pathway, and downstream effects include the enhancement of MnSOD and inhibition of mPTP.

MAKAP - A master scaffold for cardiac remodeling

Abstract: Cardiac remodeling is regulated by an extensive intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cellular adaptation. In the last few years, it has become apparent that multimolecular signaling complexes or ‘signalosomes’ are important for fidelity in intracellular signaling and for mediating crosstalk between the different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPβ serves as a scaffold for a large signalosome that is responsive to cAMP, calcium, hypoxia, and mitogen-activated protein kinase signaling. The main function of mAKAPβ signalosomes is to modulate stress-related gene expression regulated by the transcription factors NFATc, MEF2 and HIF-1α and type II histone deacetylases that control pathological cardiac hypertrophy.

Cytoprotection of baicalein against oxidative stress-induced cardiomyocytes injury through the Nrf2/Keap1 pathway.

Abstract: Baicalein is one of the major flavonoids found in the rootof Scutellaria baicalensis Georgi. Previous studies suggest that bai-calein displays protective effect on experimental cardiac modelsin vitro and in vivo. However, the mode of action remains unclear.Here, we showed that baicalein conferred cardioprotective effectagainst oxidative stress-induced cell injury in H9c2 cells and humanembryonic stem cells-derived cardiomyocytes. Immunoprecipitationwith anti-NF-E2–related factor 2 (Nrf2) antibody in baicalein-treatedcells demonstrated that baicalein effectively disrupted the associationbetween Nrf2 and Kelch-like epichlorohydrin-associated protein1 (Keap1). In addition, the unbounded Nrf2 translocated from cyto-plasm to nucleus and increased Nrf2/heme oxygenase-1 (HO-1) con-tent in a time-dependent manner. Moreover, antioxidant responseelement transcriptional activity was enhanced by baicalein treatment,and the Nrf2 siRNA transfection could block the cytoprotectiveeffect of baicalein. Taken together, these results demonstrate thatbaicalein protected cardiomyocytes against oxidative stress-inducedcell injury through the Nrf2/Keap1 pathway.Key Words: baicalein, cardioprotection, oxidative stress, Nrf2(J Cardiovasc Pharmacol 2015;65:39–46)

Vascular Effects of Endothelin Receptor Antagonists Depends on Their Selectivity for ETA Versus ETB Receptors and on the Functionality of Endothelial ETB Receptors

Abstract: The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs). Methods: The contribution of the ETB receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ETB receptors is different in pathological vis-a-vis normal conditions, we compared the efficacy of ETA-selective and dual ETA/ETB ERAs on blood pressure in hypertensive rats equipped with telemetry.

First-in-man Study With Inclacumab, a Human Monoclonal Antibody Against P-selectin

Abstract: P-selectin, a cell adhesion molecule, is a component of the membrane of the α-granules of platelets and Weibel–Palade bodies of endothelial cells. On cellular activation, it can be rapidly translocated to the cell surface. Through interactions with its ligand, P-selectin glycoprotein ligand 1, P-selectin plays a critical role in leukocyte tethering and rolling on the vessel wall and subsequent extravasation. It also promotes platelet rolling and adhesion to the activated vessel wall.1–5 A truncated soluble form of P-selectin, which is either released by proteolytic cleavage of the cell-expressed P-selectin or by secretion of an alternatively spliced form of P-selectin lacking the cytoplasmic domain, is circulating in blood.6–8 Soluble P-selectin has been shown to exert prothrombotic and procoagulant activities.9,10 P-selectin plays therefore a role at the interface of inflammation and thrombosis. In clinics, increased expression of P-selectin on endothelial cells and/or platelets as well as increased plasma concentrations of soluble P-selectin has been reported in a variety of cardiovascular disorders, including peripheral arterial disease,11 coronary artery diseases,12,13 diabetes,14 hypertension,15 hypercholesterolemia,16 venous thromboembolism,17 and atrial fibrillation.18 In animal models, blockade of P-selectin functions has been shown to inhibit atherosclerosis development,11,19 thrombus growth and fibrin deposition,20,21 and ischemia-induced tissue injury.22,23 Inclacumab is a recombinant human monoclonal antibody of the immunoglobulin G4 subclass directed against human P-selectin, which is expressed in Chinese hamster ovarian cell line. It has 2 single point mutations (L235E, S228P) introduced into the Fc part to avoid antibody-dependent cell-mediated cytotoxicity and to improve structural stability. The variable regions were derived from transgenic mice that were immunized with soluble P-selectin antigen (technology licensed by Genmab A/S) and the resulting hybridoma. It binds to human P-selectin with high affinity (in nM range) and shows selectivity for P-selectin (>3000-fold) compared with the other members of the selectin family (E-selectin and L-selectin). This selectivity is an essential safety requirement because blockade of P-selectin and E-selectin or of P-selectin and L-selectin results in an immunocompromised phenotype based on evidence from double-selectin knockout mice.24 Inclacumab inhibits P-selectin–mediated functions and has been shown to exert antiinflammatory and antithrombotic activity. It inhibited the adhesion of leukocytes to endothelial cells in an ex vivo human flow system and reduced the infiltration of leukocytes into a nonhuman primate inflammation model. Furthermore, it attenuated leukocyte adhesion to platelet monolayers ex vivo and formation of platelet–leukocyte aggregates (PLA).25 Through its inhibitory effects on inflammatory and thrombotic cascades, inclacumab is expected to beneficially interfere with the basic events underlying atherosclerosis. It is therefore being developed for the treatment and prevention of atherosclerotic cardiovascular diseases. First indication of its efficacy in clinics was obtained in a recently completed trial,26 where it seemed to reduce the myocardial damage after percutaneous coronary intervention in non–ST-segment elevation myocardial infarction patients. The present single ascending dose study was the first clinical study carried out with inclacumab to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects. Results of this study provided rationale for the selection of doses in the proof-of-concept trial.

Flavonols in the prevention of diabetes-induced vascular dysfunction

Abstract: As flavonols are present in fruits and vegetables, they are consumed in considerable amounts in the diet. There is growing evidence that the well-recognized antioxidant, anti-inflammatory, and vasorelaxant actions of flavonols may, at least in part, result from modulation of biochemical signaling pathways and kinases. It is well established that diabetes is associated with increased cardiovascular morbidity and mortality. Despite clinical management of blood glucose levels, diabetes often results in cardiovascular disease. There is good evidence that endothelial dysfunction contributes significantly to the progression of diabetic cardiovascular diseases. This review describes the biological actions of flavonols that may ameliorate adverse cardiovascular events in diabetes. We discuss evidence that flavonols may be developed as novel pharmacological agents to prevent diabetes-induced vascular dysfunction.

Omecamtiv mecarbil, a cardiac myosin activator, increases Ca2+ sensitivity in myofilaments with a dilated cardiomyopathy mutant tropomyosin E54K

Abstract: Apart from transplant, there are no satisfactory therapies for the severe depression in contractility in familial dilated cardiomyopathy (DCM). Current heart failure treatments that act by increasing contractility involve signaling cascades that alter calcium homeostasis and induce arrhythmias. Omecamtiv mecarbil is a promising new inotropic agent developed for heart failure that may circumvent such limitations. Omecamtiv is a direct cardiac myosin activator that promotes and prolongs the strong myosin-actin binding conformation to increase the duration of systolic elastance. We tested the effect of omecamtiv on Ca(2+) sensitivity of myofilaments of a DCM mouse model containing a tropomyosin E54K mutation. We compared tension and ATPase activity of detergent-extracted myofilaments with and without treatment with 316 nM omecamtiv at varying pCa values. When transgenic myofilaments were treated with omecamtiv, the pCa50 for activation of tension increased from 5.70 ± 0.02 to 5.82 ± 0.02 and ATPase activity increased from 5.73 ± 0.06 to 6.07 ± 0.04. This significant leftward shift restored Ca(2+) sensitivity to levels no longer significantly different from controls. Proteomic studies lacked changes in sarcomeric protein phosphorylation. Our data demonstrate that omecamtiv can potentially augment cardiac contractility in DCM by increasing Ca(2+) sensitivity. The use of direct myosin activators addresses functional defects without incurring the adverse side effects of Ca(2+)-dependent treatments.

MicroRNA Signature and Cardiovascular Dysfunction.

Abstract: The worldwide increase in the prevalence of obesity and type 2 diabetes and the associated elevated risk of cardiovascular disease (CVD) has emphasized the need to seek new therapeutic targets to offset the negative impact on human health outcomes. In this regards, microRNAs (miRNAs), a class of small noncoding RNAs that mediate posttranscriptional gene silencing, have received considerable interest. miRNAs repress gene expression by their ability to pair with target sequences in the 3' untranslated region of the messenger RNA. miRNAs play a crucial role in the biogenesis and function of the cardiovascular system and are implicated as dynamic regulators of cardiac and vascular signaling and pathophysiology. Numerous miRNAs have been identified as novel biomarkers and potential therapeutic targets for CVD. In this review, we discuss the contribution of miRNAs to the regulation of CVD, their role in macrovascular/microvascular (dys)function, their potential as important biomarkers for the early detection of CVD, and, finally, as therapeutic targets.

Cytoprotective Role of Alpha-1 Antitrypsin in Vascular Endothelial Cell Under Hypoxia/Reoxygenation Condition.

Abstract: Ischemia/reperfusion (IR) injury is a critical factor in the pathogenesis of tissue injury after myocardial infarction, multiple organ failure, and other acute ischemic events. Previous studies suggest that α1-antitrypsin (AAT) plays a cytoprotective role in beta cells and human pulmonary cells. We hypothesize that AAT may have the potential to reduce IR-induced vascular injury involved in cell apoptosis and permeability. In this study, we investigate the role of AAT in human umbilical vein endothelial cells using a model wherein endothelial cell monolayers are exposed to hypoxia/reoxygenation (HR). We found that exogenous AAT alleviated HR injury in a dose- and time-dependent manner. Furthermore, by gain and loss function experiments, we demonstrated that overexpression of AAT decreased cell apoptosis and promoted proliferation by inhibiting Rac1/PAK/p38 signaling and against oxidative stress, and also reduced cellular permeability by increasing ZO-1 and occludin expression. Thus, we provided evidences to illustrate that AAT played a cytoprotective role in vascular endothelial cell under HR condition, suggesting that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular injury.

Diosgenin Mitigates Streptozotocin Diabetes-induced Vascular Dysfunction of the Rat Aorta: The Involved Mechanisms.

Abstract: Chronic diabetes mellitus finally leads to serious vascular dysfunction. Diosgenin is a natural steroidal saponin with potential cardiovascular protective effect. In this study, the protective effect of diosgenin was checked on the aorta from streptozotocin-induced diabetic rats. Diabetic rats received diosgenin (40 mg·kg·d) for 7 weeks starting 1 week after intraperitoneal injection of streptozotocin (60 mg/kg). Aortic reactivity of endothelium-intact and -denuded rings to potassium chloride, phenylephrine, acetylcholine, and isosorbide dinitrate were measured and some involved mechanisms were explored. The results showed that diosgenin has a hypoglycemic effect and attenuates maximum contractile response of endothelium-intact and -denuded rings to PE. In addition, endothelium-dependent relaxation to acetylcholine was greater in diosgenin-treated diabetics with no significant change for endothelium-independent relaxation to isosorbide dinitrate and addition of N(G)-nitro-L-arginine methyl ester, as a nitric oxide synthase inhibitor eliminated this beneficial effect. Furthermore, diosgenin significantly attenuated aortic DNA fragmentation as an index of apoptosis and malondialdehyde content, lowered the aortic expression of angiotensin converting enzyme and transcription factor nuclear factor-κB and raised expression of endothelial nitric oxide synthase with no significant effect on the activity of superoxide dismutase. Taken together, our study provides insight into the mechanisms underlying the beneficial effect of diosgenin as a potential therapeutic agent to mitigate vascular dysfunction in diabetes mellitus.

Cerebral circulation: function and dysfunction in Alzheimer's disease.

Abstract: Alzheimer's disease is a neurodegenerative disease associated with a cerebrovascular pathology partly imputed to increased brain levels of amyloid beta (Aβ) peptide and transforming growth factor-β1 (TGF-β1). Using transgenic mice that overproduce Aβ (APP mice) or TGF-β1 (TGF mice), we found that both induce impairments of cerebrovascular function and structural changes of the vessel wall. Soluble Aβ species affect blood vessel primarily by increasing oxidative stress, which results in reduced nitric oxide-mediated dilations and impaired signaling of endothelial transient receptor potential vanilloid type 4 and smooth muscle KATP channels. These impairments occur early in the disease process and can be rescued by either antioxidants (Tempol, N-acetylcysteine) or therapy with antioxidant properties (simvastatin). In contrast, comparable impairments in TGF mice were insensitive to antioxidants and could only be rescued by therapy with pleiotropic effects. The blood flow response evoked by whisker stimulation was impaired in both APP and TGF mice. In contrast, the cerebral uptake of glucose induced by this stimulus was reduced only in APP mice, pointing to preserved neuronal function in the TGF mice. Accordingly, despite similar but mechanistically different cerebrovascular deficits in APP and TGF mice, overt cognitive deficits were seen only in APP mice and could be rescued depending on age.

Nuclear G protein signaling: new tricks for old dogs.

Abstract: According to the standard model of G protein-coupled receptor (GPCR) signaling, GPCRs are localized to the cell membrane where they respond to extracellular signals. Stimulation of GPCRs leads to the activation of heterotrimeric G proteins and their intracellular signaling pathways. However, this model fails to accommodate GPCRs, G proteins, and their downstream effectors that are found on the nuclear membrane or in the nucleus. Evidence from isolated nuclei indicates the presence of GPCRs on the nuclear membrane that can activate similar G protein-dependent signaling pathways in the nucleus as at the cell surface. These pathways also include activation of cyclic adenosine monophosphate, calcium and nitric oxide synthase signaling in cardiomyocytes. In addition, a number of distinct heterotrimeric and monomeric G proteins have been found in the nucleus of various cell types. This review will focus on understanding the function of nuclear G proteins with a focus on cardiac signaling where applicable.

Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy.

Abstract: Small-conductance Ca(2+)-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle.

Nuclear calcium in cardiac myocytes

Abstract: Calcium (Ca) is a universal second messenger involved in the regulation of various cellular processes, including electrical signaling, contraction, secretion, memory, gene transcription, and cell death. In heart, Ca governs cardiomyocyte contraction, is central in electrophysiological properties, and controls major signaling pathway implicated in gene transcription. How cardiomyocytes decode Ca signal to regulate gene expression without interfering with, or being controlled by, "contractile" Ca that floods the entire cytosol during each heartbeat is still elusive. In this review, we summarize recent findings on nuclear Ca regulation and its downstream signaling in cardiomyocytes. We will address difficulties in reliable quantification of nuclear Ca fluxes and discuss its role in the development and progression of cardiac hypertrophy and heart failure. We also point out key open questions to stimulate future work.

Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.

Abstract: Aims:We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling.Me

Digoxin Is Associated With Increased All-cause Mortality in Patients With Atrial Fibrillation Regardless of Concomitant Heart Failure: A Meta-analysis.

Abstract: For decades, digoxin has been widely used to control ventricular rate in atrial fibrillation (AF). However, it remains controversial as to whether digoxin is associated with increased mortality in AF. In this study, we searched relevant studies that were published before December 1, 2014, in PubMed, EMBASE, and the Cochrane central databases. We systematically reviewed the references and performed a meta-analysis of 8 carefully selected studies with 302,738 patients who were included for the final analysis. It was shown that digoxin use was associated with increased risk of all-cause mortality in AF overall [hazard ratio (HR) = 1.375, 95% confidence intervals (CI), 1.201-1.574, P = 0.0001]. Subgroup analysis further revealed that digoxin was associated with increased all-cause mortality in patients with AF, which was complicated by heart failure (HF) (HR = 1.201, CI, 1.074- 1.344, P = 0.001), and in those subjects without HF (HR = 1.172, CI, 1.148-1.198, P = 0.0001). Sensitivity analyses found results to be robust. Our findings indicated that digoxin use was associated with significantly increased all-cause mortality in patients with AF regardless of concomitant HF. We suggest that digoxin should not be preferentially used over other rate control medications in AF.

Neutrophil Gelatinase-associated Lipocalin in the Prediction of Contrast-induced Nephropathy: A Systemic Review and Meta-analysis.

Abstract: Objective:The aim of this study was to investigate the predictive value of neutrophil gelatinase-associated lipocalin (NGAL) in the early diagnosis of contrast-induced nephropathy (CIN).Methods:We searched MEDLINE and Embase until December 2014 for articles evaluating the diagnostic accuracy of plas

Third-hand Smoke: Impact on Hemostasis and Thrombogenesis.

Abstract: Cigarette smoking is a major risk factor for acute coronary thrombosis. In fact, both active/first-hand smoke and passive/second-hand smoke exposure are known to increase the risk of coronary thrombosis. Although recently a new risk has been identified and termed third-hand smoke (THS), which is the residual tobacco smoke contaminant that remains after a cigarette is extinguished, it remains to be determined whether it can also enhance the risk of thrombogenesis, much like first-hand smoke and second-hand smoke. Therefore, the present studies investigated the impact of THS exposure in the context of platelet biology and related disease states. It was found that THS-exposed mice exhibited an enhanced platelet aggregation and secretion responses as well as enhanced integrin GPIIb-IIIa activation. Furthermore, it was found that THS exposure shortens the tail bleeding time and the occlusion time in a model of thrombosis. Thus, our data demonstrate for the first time (at least in mice) that THS exposure increases the risk of thrombosis-based disease states, which is attributed, at least in part, to their hyperactive platelets.

A nonpeptide angiotensin II type 2 receptor agonist prevents renal inflammation in early diabetes.

Abstract: We hypothesized that direct AT2R stimulation improves albuminuria in diabetes by preventing renal inflammation and improving oxidative stress. Normoglycemic controls (NCs) and streptozotocin-induced diabetes Sprague-Dawley rats (DM) were treated for 4 weeks with vehicle (V) or the AT2R agonist Compound 21 (C21). At the end of study, we evaluated blood pressure, urinary albumin to creatinine ratio (UACR), renal interstitial fluid (RIF) levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nitric oxide (NO), cGMP, and 8-isoprostane, and renal expression of TNF-α, IL-6, and AT2R. There were no significant differences in blood pressure between different treatments. DM rats demonstrated increased UACR, RIF TNF-α, IL-6 and 8-isoprostane, and messenger RNA (mRNA) for TNF-α and IL-6. DM rats also had reduced RIF NO and cGMP. C21 treatment of DM rats limited the increase in UACR, normalized RIF TNF-α, IL-6 and 8-isoprostane, and in mRNA for TNF-α and IL-6, and increased RIF NO and cGMP. In NC rats, C21 treatment did not change these parameters. AT2R mRNA and protein expressions increased in DM rats compared with NC but were not influenced by C21 treatment. We conclude that direct AT2R stimulation in diabetic rats improves diabetic albuminuria through the prevention of renal inflammation and improved production of NO and cGMP.

EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade

Abstract: To determine whether the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation, and cardiac stress, erlotinib was administered to rats (10 mg · kg(-1)· d(-1)) for 9 weeks Plasma magnesium decreased progressively between 3 and 9 weeks (-9% to -26%) Modest increases in plasma substance P (SP) occurred at 3 (27%) and 9 (25%) weeks Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac perivascular nitrotyrosine The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg · kg(-1) · d(-1)), attenuated erlotinib-induced hypomagnesemia up to 42%, reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (-11%) and % fractional shortening (-17%) by 7 weeks of erlotinib treatment and significant reduction (-175%) in mitral valve E/A ratio at week 9 indicative of systolic and early diastolic dysfunction Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction and partially attenuated the anatomical changes Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress and mild-to-moderate cardiac dysfunction, which can largely be corrected by the administration of the SP receptor blocker

G protein-coupled receptor signaling in cardiac nuclear membranes.

Abstract: G protein-coupled receptors (GPCRs) play key physiological roles and represent a significant target for drug development. However, historically, drugs were developed with the understanding that GPCRs as a therapeutic target exist solely on cell surface membranes. More recently, GPCRs have been detected on intracellular membranes, including the nuclear membrane, and the concept that intracellular GPCRs are functional is become more widely accepted. Nuclear GPCRs couple to effectors and regulate signaling pathways, analogous to their counterparts at the cell surface, but may serve distinct biological roles. Hence, the physiological responses mediated by GPCR ligands, or pharmacological agents, result from the integration of their actions at extracellular and intracellular receptors. The net effect depends on the ability of a given ligand or drug to access intracellular receptors, as dictated by its structure, lipophilic properties, and affinity for nuclear receptors. This review will discuss angiotensin II, endothelin, and β-adrenergic receptors located on the nuclear envelope in cardiac cells in terms of their origin, activation, and role in cardiovascular function and pathology.

MicroRNA-101 inhibits rat cardiac hypertrophy by targeting Rab1a.

Abstract: Cardiac hypertrophy is a primary pathological change associated with cardiovascular diseases. Dysregulated microRNAs are frequent in cardiovascular diseases and contribute to cardiac hypertrophy by regulating a series of targeted genes. In this study, a rat model of cardiac hypertrophy was created by transverse abdominal aortic constriction, and cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes was induced using angiotensin II (AngII) to investigate the role of miR-101 in myocardial hypertrophy. We demonstrated that miR-101 was downregulated in both the transverse abdominal aortic constriction rat model and hypertrophic cardiac myocytes. The overexpression of miR-101 in neonatal rat cardiomyocytes, which was accompanied by a reduced Rab1a level, inhibits 3 cardinal features of cardiomyocyte hypertrophy: fetal gene expression, protein synthesis, and cell enlargement. Conversely, the downregulation of miR-101 reverses these effects. Furthermore, the luciferase reporter system demonstrated that Rab1a is a target gene of miR-101, and the ectopic expression of Rab1a can reverse the cardiomyocyte hypertrophy inhibitory activity of miR-101. Taken together, our findings identify miR-101 as an important regulator in cardiac hypertrophy and implicate the potential application of miR-101 in the therapy of cardiac hypertrophy.