Molecular regulation of cardiac hypertrophy

Barry, Seán P.; Davidson, Sean M.; Townsend, Paul A.

doi:10.1016/j.biocel.2008.02.020

Cited by 258 publications

(203 citation statements)

References 179 publications

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“…Cyclic Stretch Potentiates Pathological Gene Expression. We asked if cyclic stretch would trigger known genetic indicators of pathological remodeling (30). We collected and amplified mRNA from conditioned tissues after 6, 24, and 96 h in culture and used Affymetrix whole-transcript microarrays to determine gene expression values.…”

Section: Resultsmentioning

confidence: 99%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

124

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The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structurefunction relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α-to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart. organs on chips | mechanotransduction | muscular thin films | microarray | contraction

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Section: Resultsmentioning

confidence: 99%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

124

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show abstract

“…The ERK1/2 cascade has been reported to be activated and to be involved in diverse instances of cardiac hypertrophy and heart failure including cardiomyopathies, both in rodents and humans, and has, thus, been considered as a putative therapeutic target in pathological hypertrophy (6,(33)(34)(35). However, many mouse models point toward a pivotal role of ERK1/2 in the prevention of apoptotic cell death: cell death is significantly increased in mice with cardiac overexpression of dominant-negative Raf1, in mice treated with MEK1/2-inhibitors, and in ERK1 −/− ERK2 +/− mice (11,12,36), whereas overexpression of constitutively active MEK1 increases cell survival (37,38).…”

Section: Discussionmentioning

confidence: 99%

Interference with ERK ^Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

Ruppert

Deiss

Herrmann³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK Thr188 autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK Thr188 phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK Thr188 phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2 T188A , which is dominant-negative for ERK Thr188 signaling. ERK2 T188A efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2 T188A did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERK Thr188 phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK Thr188 phosphorylation was increased 8.5 ± 1.3-fold in high-gradient, rapidly progressing cases (≥40 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERK Thr188 phosphorylation (i) inhibits pathological hypertrophy and (ii) does not impair antiapoptotic ERK1/2 signaling and because ERK Thr188 phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK Thr188 phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.MAPK | apoptosis | GPCRs C ardiac hypertrophy has been identified as an independent risk factor of diastolic dysfunction, heart failure, arrhythmias, and sudden death (1). Various triggers initiate cardiac hypertrophy, but the type of trigger has been identified as decisive for an adaptive vs. a maladaptive outcome of cardiac hypertrophy. Whereas cardiovascular diseases such as hypertension, aortic stenosis, or myocardial infarction generally induce a pathological type of hypertrophy, chronic physical exercise or postnatal cardiac growth entail a compensatory and physiological type of hypertrophy. In contrast to physiological hypertrophy, pathological hypertrophy is characterized by accumulation of interstitial collagen and cell death, which both have been shown to contribute to increased cardiovascular risk (2-5). Therefore, it would be of great therapeutic interest to prevent pathological hypertrophy; however, such prevention requires a fine balance between inhibition of maladaptive and preservation of compensatory adaptive hypertrophy.Hypertrophic stimuli are mediated via several intracell...

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“…Here, we focus on agents that modulate the function of myosin or the troponin complex, the only sarcomeric proteins successfully targeted to date. Sarcomere function is also affected by calcium handling [12][13][14] , metabolism 15,16 and muscle atrophy or hypertrophy [17][18][19] , and these have been extensively reviewed elsewhere.…”

Section: Positive Inotropesmentioning

confidence: 99%

Targeting the sarcomere to correct muscle function

Hwang

Sykes

2015

Nat Rev Drug Discov

111

122

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Molecular regulation of cardiac hypertrophy

Cited by 258 publications

References 179 publications

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

Interference with ERK ^Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

Targeting the sarcomere to correct muscle function

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Molecular regulation of cardiac hypertrophy

Cited by 258 publications

References 179 publications

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

Interference with ERK Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

Targeting the sarcomere to correct muscle function

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Product

Resources

About

Interference with ERK ^Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy