A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.

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Oxygen, oxidative stress, hypoxia, and heart failure

The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.

Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading

When the heart faces a hemodynamic burden, it can do the following to compensate: (1) use the Frank-Starling mechanism to increase crossbridge formation; (2) augment muscle mass to bear the extra load; and (3) recruit neurohormonal mechanisms to increase contractility. The first mechanism is limited in its scope, and the third is deleterious as a chronic adjustment. Thus, increasing mass assumes a key role in the compensation for hemodynamic overload. This increase in mass is due to the hypertrophy of existing myocytes rather than hyperplasia, because cardiomyocytes become terminally differentiated soon after birth. In response to pressure overload in conditions such as aortic stenosis or hypertension, the parallel addition of sarcomeres causes an increase in myocyte width, which in turn increases wall thickness. This remodeling results in concentric hypertrophy (increase in ratio of wall thickness/chamber dimension).

According to LaPlace’s Law, the load on any region of the myocardium is given as follows: (pressure×radius)/(2×wall thickness); thus, an increase in pressure can be offset by an increase in wall thickness. Because systolic stress (afterload) is a major determinant of ejection performance, the normalization of systolic stress helps maintain a normal ejection fraction even when needing to generate high levels of systolic pressure.1 Volume overload in conditions such as chronic aortic regurgitation, mitral regurgitation, or anemia engenders myocyte lengthening by sarcomere replication in series and an increase in ventricular volume. This pattern of eccentric hypertrophy (cavity dilatation with a decrease in ratio of wall thickness/chamber dimension) is also initially compensatory, such that the heart can meet the demand to sustain a high stroke volume. However, chronic hypertrophy may be deleterious because it increases the risk for the development of heart failure and premature death.

This review will focus on the pathogenesis of pressure- versus volume-overload types of left ventricular hypertrophy (LVH), detection, …

Left Ventricular Hypertrophy Pathogenesis, Detection, and Prognosis

Matrix metalloproteinases (MMPs) are a major group of enzymes that regulate cell-matrix composition. MMP genes show a highly conserved modular structure. Ample evidence exists on the role of MMPs in normal and pathological processes, including embryogenesis, wound healing, inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. The expression patterns of MMPs have interesting implications for the use of MMP inhibitors as therapeutic agents. Insights might be gained as to the preference for a general MMP inhibitor as opposed to an inhibitor designed to be specific for certain MMP family members as it relates to a defined disease state, and may give clues to potential side effects. The signalling pathways that lead to induction of expression of MMPs are still incompletely understood, but certain patterns are beginning to emerge. Regarding inhibition of MMP expression at the level of kinase pathways, it is possible that selective chemical inhibitors for distinct signalling pathways (e.g. MAPK, PKC) will hopefully, soon be available for initial clinical trials. Overexpression of selective dual specificity MAPK phosphatases have been shown to prevent MMP promoter activation which could also be used as a novel strategy to prevent activation of AP-1 and ETS transcription factors and MMP promoters in vivo. Interactions between members of different transcription factors provide fine-tuning of the transcriptional regulation of MMP promoter activity. MMPs play a crucial role in tumor invasion. Although the expression of MMPs in malignancies has been studied widely, the specific role of distinct MMPs in the progression of cancer may be more complex than has been assumed. For example, it has recently been shown that MMP-3, MMP-7, MMP-9 and MMP-12 can generate angiostatin from plasminogen, indicating that their expression in peritumoral area may in fact serve to limit angiogenesis and thereby inhibit tumor growth and invasion. The recent view about the role of stromal cells in the progression of cancer cell growth and metastasis is particularly interesting, and additional studies about the regulation of MMP gene expression and activity in malignancies are needed to understand the role and regulation of MMPs in tumor cell invasion.

Regulation of matrix metalloproteinases: an overview.

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

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The pathogenesis of cardiac fibrosis

The role of tumor necrosis factor in the pathophysiology of heart failure.

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

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Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.

Background—Extracellular matrix turnover is regulated by matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs). Together, these proteins may contribute to myocardial remodeling in congestive heart failure. We hypothesized that the expression of MMPs and TIMPs might be differentially regulated in the failing human heart. Methods and Results—Northern blot analyses were performed with probes to TIMP-1 to -4 and GAPDH with poly A+ mRNA from ventricular tissues of patients with ischemic cardiomyopathy (ICM, n=16) or idiopathic dilated cardiomyopathy (DCM, n=15) and nonfailing control hearts (n=15). TIMP-1 to -4 and MMP-9 proteins were quantified by ELISA and/or Western blot, and the total gelatinolytic activity was studied by gelatin zymography. The results showed that cardiac expression of TIMP-1 and -3 transcripts and proteins was significantly reduced in ICM and DCM. No significant difference was observed in TIMP-2 and -4 transcripts. However, TIMP-4 protein was si...

Differential Expression of Tissue Inhibitors of Metalloproteinases in the Failing Human Heart

Myocardial fibrosis caused by maladaptive extracellular matrix (ECM) remodeling is implicated in the dysfunction of the failing heart. Matrix metalloproteinases (MMPs) regulate ECM remodeling, and are regulated by cytokines. Transgenic mice with cardiac-specific overexpression of tumor necrosis factor alpha (TNF-alpha) (TNF1.6) develop heart failure. We hypothesized that modulation of TNF-alpha and/or MMP activity might alter the myocardial ECM remodeling process and the development of heart failure. To test this hypothesis, we took advantage of the TNF1.6 mice and studied soluble and total collagens and collagen type profiling by using hydroxyproline quantification, Sircol collagen assay, Northern blot analysis, and immunohistochemistry and studied myocardial function by using echocardiography. Progressive ventricular hypertrophy and dilation in the TNF1.6 mice were accompanied by a significant increase in MMP-2 and MMP-9 activity, an increase in collagen synthesis, deposition, and denaturation, and a decrease in undenatured collagens. In young TNF1.6 mice, these changes in the ECM were associated with marked diastolic dysfunction as demonstrated by significantly reduced transmitral Doppler echocardiographic E/A wave ratio. Anti-TNF-alpha treatment with adenoviral vector expressing soluble TNF-alpha receptor type I attenuated both MMP-2 and MMP-9 activity, prevented further collagen synthesis, deposition and denaturation, and preserved myocardial diastolic function in young, but not old, TNF1.6 mice. The results suggest a critical role of TNF-alpha and MMPs in myocardial matrix remodeling and functional regulation and support the hypothesis that both TNF-alpha and MMPs may serve as potential therapeutic targets in the treatment of heart failure.

https://www.pnas.org/content/pnas/97/23/12746.full.pdf

Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy.

Background— Left ventricular assist device (LVAD) support of the failing heart induces salutary changes in myocardial structure and function. Matrix metalloproteinases (MMPs) are increased in the failing heart and are induced by stretch in cardiac cells in vitro. We hypothesized that mechanical unloading may affect LV plasticity by regulating MMPs and their substrates. Methods and Results— LV samples were collected from patients with dilated cardiomyopathy (DCM, n=14) or ischemic cardiomyopathy (ICM, n=16) at the time of implantation of the LVAD and again during cardiac transplantation. MMP-1, -3, and -9 were measured by ELISA, MMP-2 and -9 gelatinolytic activity by gelatin zymography, and tissue inhibitors of metalloproteinases (TIMPs) by Western blot. Total soluble and insoluble collagens were separated by pepsin solubilization, and the contents were determined by quantification of hydroxyproline. The undenatured soluble collagen was measured by Sircol collagen assay. The results showed that MMP-1 and -...

Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices.

Yun You Li

Papers

The role of tumor necrosis factor in the pathophysiology of heart failure.

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.

Differential Expression of Tissue Inhibitors of Metalloproteinases in the Failing Human Heart

Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy.

Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices.