Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies

Bernardo, Bianca C.; Weeks, Kate L.; Pretorius, Lynette; McMullen, Julie R.

doi:10.1016/j.pharmthera.2010.04.005

Cited by 743 publications

(768 citation statements)

References 571 publications

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“…Even though cardiac hypertrophy is a risk factor for heart failure, therapeutic prevention of cardiac hypertrophy in patients should ideally impair neither the heart's normal postnatal growth nor its adequate growth in response to exercise (3,4). Therefore, we next investigated the influence of ERK2 T188A expression on physiological growth of the heart.…”

Section: Resultsmentioning

confidence: 99%

“…Pathological hypertrophy is a key risk factor for myocardial infarction, arrhythmia, and sudden death, whereas physiological growth of the heart in response to exercise is generally accepted to be protective, i.e., to preserve or even improve heart function (1,4,26). Although maladaptive hypertrophy involves cell death, collagen deposits, fibrosis, and ventricular stiffening, these hallmarks of pathological remodeling are absent in the "athlete's" heart (1,27).…”

Section: Discussionmentioning

confidence: 99%

“…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)(3)(4)(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.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…The number of apoptotic cells depends on the plaque stage; it is generally high in advanced plaques. In this section we briefly elucidate the role of ERS in three major types of cells in atherosclerosis: smooth muscle cells (SMCs) [74] , macrophages and endothelial cells. The role of sterol regulatory element-binding proteins (SREBPs) in regulating ERS to control atherosclerosis is also discussed.…”

Section: Endoplasmic Reticulum Stress Regulates Cardiovascular Physiomentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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“…In contrast to pathological hypertrophy, this adaptation leads to maintained or even enhanced cardiac function (2,14). Hemodynamic changes of exercise-induced hypertrophy were characterized by our research group in a rat model, focusing also on the improved LV inotropic state (23).…”

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confidence: 99%

Strain and strain rate by speckle-tracking echocardiography correlate with pressure-volume loop-derived contractility indices in a rat model of athlete's heart

Kovács

Oláh

Lux

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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function is considered to be precisely measurable only by invasive hemodynamics. We aimed to correlate strain values measured by speckle-tracking echocardiography (STE) with sensitive contractility parameters of pressure-volume (P-V) analysis in a rat model of exercise-induced left ventricular (LV) hypertrophy. LV hypertrophy was induced in rats by swim training and was compared with untrained controls. Echocardiography was performed using a 13-MHz linear transducer to obtain LV long-and short-axis recordings for STE analysis (GE EchoPAC). Global longitudinal (GLS) and circumferential strain (GCS) and longitudinal (LSr) and circumferential systolic strain rate (CSr) were measured. LV P-V analysis was performed using a pressure-conductance microcatheter, and load-independent contractility indices [slope of the end-systolic P-V relationship (ESPVR), preload recruitable stroke work (PRSW), and maximal dP/dt-enddiastolic volume relationship (dP/dtmax-EDV)] were calculated. Trained rats had increased LV mass index (trained vs. control; 2.76 Ϯ 0.07 vs. 2.14 Ϯ 0.05 g/kg, P Ͻ 0.001). P-V loop-derived contractility parameters were significantly improved in the trained group (ESPVR: 3.58 Ϯ 0.22 vs. 2.51 Ϯ 0.11 mmHg/ l; PRSW: 131 Ϯ 4 vs. 104 Ϯ 2 mmHg, P Ͻ 0.01). Strain and strain rate parameters were also supernormal in trained rats (GLS: Ϫ18.8 Ϯ 0.3 vs. Ϫ15.8 Ϯ 0.4%; LSr: Ϫ5.0 Ϯ 0.2 vs. Ϫ4.1 Ϯ 0.1 Hz; GCS: Ϫ18.9 Ϯ 0.8 vs. Ϫ14.9 Ϯ 0.6%; CSr: Ϫ4.9 Ϯ 0.2 vs. Ϫ3.8 Ϯ 0.2 Hz, P Ͻ 0.01). ESPVR correlated with GLS (r ϭ Ϫ0.71) and LSr (r ϭ Ϫ0.53) and robustly with GCS (r ϭ Ϫ0.83) and CSr (r ϭ Ϫ0.75, all P Ͻ 0.05). PRSW was strongly related to GLS (r ϭ Ϫ0.64) and LSr (r ϭ Ϫ0.71, both P Ͻ 0.01). STE can be a feasible and useful method for animal experiments. In our rat model, strain and strain rate parameters closely reflected the improvement in intrinsic contractile function induced by exercise training. speckle-tracking echocardiography; pressure-volume analysis; athlete's heart; contractility; strain LONG-TERM EXERCISE TRAINING induces physiological left ventricular (LV) hypertrophy, a molecular and cellular growth process of the heart in response to altered loading conditions (6). In contrast to pathological hypertrophy, this adaptation leads to maintained or even enhanced cardiac function (2, 14). Hemodynamic changes of exercise-induced hypertrophy were characterized by our research group in a rat model, focusing also on the improved LV inotropic state (23). Contractility is the intrinsic ability of the myocardium to generate force and to shorten independently of changes in preload or afterload with fixed heart rates. In the past few decades, efforts have been made to transfer the physiological concept of contractility to the intact beating heart (4).Pressure-volume (P-V) analysis recently became the gold standard to investigate in vivo hemodynamics in animal models. During preload reduction maneuvers such as gradual occlusion of vena cava inferior, load-independent indices of myocardial contractility could be obtained (20). Th...

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Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies

Cited by 743 publications

References 571 publications

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

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

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

Strain and strain rate by speckle-tracking echocardiography correlate with pressure-volume loop-derived contractility indices in a rat model of athlete's heart

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Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies

Cited by 743 publications

References 571 publications

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

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

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

Strain and strain rate by speckle-tracking echocardiography correlate with pressure-volume loop-derived contractility indices in a rat model of athlete's heart

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

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