Focal adhesion kinase signaling in cardiac hypertrophy and failure

Franchini, Kleber G.; Clemente, Carolina F.M.Z.; Marin, Talita Miguel

doi:10.1590/s0100-879x2009000100008

Cited by 16 publications

(10 citation statements)

References 55 publications

(85 reference statements)

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“…Depletion of FAK was shown here to attenuate the hypertrophic responses of NRVM and mice left ventricle to mechanical stress, as reported previously (3,18,19). This effect has been attributed to defective activation of extracellular signal-regulated kinase 1/2, phosphatidylinositol 3-kinase/protein kinase B, and mammalian target of rapamycin/S6K signaling systems in response to mechanical stress (9,10). Apart from mediating the hypertrophic response, FAK was shown here to mediate the increases in the mitochondrial biogenesis in response to cyclic stretch.…”

Section: Discussionsupporting

confidence: 87%

A role for focal adhesion kinase in cardiac mitochondrial biogenesis induced by mechanical stress

Tornatore

Costa

Clemente

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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We studied the implication of focal adhesion kinase (FAK) in cardiac mitochondrial biogenesis induced by mechanical stress. Prolonged stretching (2-12 h) of neonatal rat ventricular myocytes (NRVM) upregulated the main components of mitochondrial transcription cascade [peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), nuclear respiratory factor (NRF-1), and mitochondrial transcription factor A]. Concomitantly, prolonged stretching enhanced mitochondrial biogenesis [copy number of mitochondrial DNA (mtDNA), content of the subunit IV of cytochrome oxidase, and mitochondrial staining-green fluorescence intensity of Mitotracker green] and induced the hypertrophic growth (cell size and atrial natriuretic peptide transcripts) of NRVM. Furthermore, the stretching of NRVM enhanced phosphorylation, nuclear localization, and association of FAK with PGC-1α. Recombinant FAK COOH-terminal, but not the NH(2)-terminal or kinase domain, precipitated PGC-1α from nuclear extracts of NRVM. Depletion of FAK by RNA interference suppressed the upregulation of PGC-1α and NRF-1 and markedly attenuated the enhanced mitochondrial biogenesis and hypertrophic growth of stretched NRVM. In the context of energy metabolism, FAK depletion became manifest by a reduction of ATP levels in stretched NRVM. Complementary studies in adult mice left ventricle demonstrated that pressure overload upregulated PGC-1α, NRF-1, and mtDNA. In vivo FAK silencing transiently attenuated the upregulation of PGC-1α, NRF-1, and mtDNA, as well as the left ventricular hypertrophy induced by pressure overload. In conclusion, activation of FAK signaling seems to be important for conferring enhanced mitochondrial biogenesis coupled to the hypertrophic growth of cardiomyocytes in response to mechanical stress, via control of mitochondrial transcription cascade.

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Section: Discussionsupporting

confidence: 87%

A role for focal adhesion kinase in cardiac mitochondrial biogenesis induced by mechanical stress

Tornatore

Costa

Clemente

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…For example, the ability of calpains to degrade focal adhesion kinase, calcineurin, and caspases is striking given the prominent role these proteins play in cardiac hypertrophy. Focal adhesion kinase is a broadly expressed tyrosine kinase that detects biomechanical stress and then signals to induce cardiac hypertrophy 79, 82 Subsequent calpain activation caused by this cardiac hypertrophy, could result in the degradation of focal adhesion kinase (or calcineurin, another purported calpain substrate) thereby explaining, in part, the inhibitory effect that calpain activation has on cardiac hypertrophy development 82, 83 . Alternatively, if increased calpain activity enhances the degradation of caspases in cardiac hypertrophy, protection against cell death and development of cardiac hypertrophy might occur, confounding our understanding of how degradation of these reported calpain substrates might effect cardiac hypertrophy.…”

Section: The Role Of Calpains In Protein Degradation In Cardiac Hypermentioning

confidence: 99%

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et al. 2011

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Cardiac hypertrophy develops most commonly in response to hypertension and is an independent risk factor for the development of heart failure. The mechanisms by which cardiac hypertrophy may be reversed to reduce this risk have not been fully determined to the point where mechanism-specific therapies have been developed. Recently, proteases in the calpain family have been implicated in regulating the development of cardiac hypertrophy in preclinical animal models. In this review, we summarize the molecular mechanisms by which calpain inhibition has been shown to modulate the development of cardiac (specifically ventricular) hypertrophy. The context within which calpain inhibition might be developed for therapeutic intervention of cardiac hypertrophy is then discussed.

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“…In line with these findings, pre-administration of calpeptin, a specific calpain inhibitor, to hypertensive β3-integrin-deficient mice alleviated cardiomyocyte apoptosis and prevented cardiac hypertrophy [184]. Another study suggested that elevated calpain activation in hypertrophic heart could lead to the degradation of focal adhesion kinase as well as calcineurin to worsen cardiac hypertrophic response [185]. Treatment with calpain inhibitor attenuated cardiac hypertrophy via inhibiting the degradation of these proteins.…”

Section: Role Of Proteases In Cardiometabolic Diseasesmentioning

confidence: 91%

Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications

Hua

Nair

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cardiovascular disease is the leading cause of death in the U.S. and other developed country. Metabolic syndrome, including obesity, diabetes/insulin resistance, hypertension and dyslipidemia is major threat for public health in the modern society. It is well established that metabolic syndrome contributes to the development of cardiovascular disease collective called as cardiometabolic disease. Despite documented studies in the research field of cardiometabolic disease, the underlying mechanisms are far from clear. Proteases are enzymes that break down proteins, many of which have been implicated in various diseases including cardiac disease. Matrix metalloproteinase (MMP), calpain, cathepsin and caspase are among the major proteases involved in cardiac remodeling. Recent studies have also implicated proteases in the pathogenesis of cardiometabolic disease. Elevated expression and activities of proteases in atherosclerosis, coronary heart disease, obesity/insulin-associated heart disease as well as hypertensive heart disease have been documented. Furthermore, transgenic animals that are deficient in or overexpress proteases allow scientists to understand the causal relationship between proteases and cardiometabolic disease. Mechanistically, MMPs and cathepsins exert their effect on cardiometabolic diseases mainly through modifying the extracellular matrix. However, MMP and cathepsin are also reported to affect intracellular proteins, by which they contribute to the development of cardiometabolic diseases. On the other hand, activation of calpain and caspases has been shown to influence intracellular signaling cascade including the NF-κB and apoptosis pathways. Clinically, proteases are reported to function as biomarkers of cardiometabolic diseases. More importantly, the inhibitors of proteases are credited with beneficial cardiometabolic profile, although the exact molecular mechanisms underlying these salutary effects are still under investigation. A better understanding of the role of MMPs, cathepsins, calpains and caspases in cardiometabolic diseases process may yield novel therapeutic targets for threating or controlling these diseases.

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Focal adhesion kinase signaling in cardiac hypertrophy and failure

Cited by 16 publications

References 55 publications

A role for focal adhesion kinase in cardiac mitochondrial biogenesis induced by mechanical stress

A role for focal adhesion kinase in cardiac mitochondrial biogenesis induced by mechanical stress

Tear Me Down

Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications

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