Endogenous inhibitors of hypertrophy in concentric versus eccentric hypertrophy

Abstract

Left ventricular (LV) hypertrophy (LVH) is an adaptive response to hemodynamic overload, but also contributes to the pathogenesis of heart failure. LVH can be concentric (cLVH) but subsequent dilatation and progression to eccentric hypertrophy (eLVH) may lead to global pump failure. Recently, several endogenous molecular inhibitors of hypertrophy have been identified. Using real-time PCR, we compared the myocardial mRNA expression of these inhibitors in pressure-overload induced cLVH (severe aortic stenosis) and in volume overloadinduced eLVH (severe mitral regurgitation) in patients, and during the progression from cLVH to eLVH in pressure overload in rat. Each of these genes showed a unique temporal expression profile. Strikingly, except for SOCS-3, changes in gene expression of these negative regulators in rat cLVH and eLVH vs sham were recapitulated in human cLVH and eLVH. In particular, VDUP-1 and MCIP-1 were high in cLVH but expression levels were normal in eLVH, both in rat and human. These data indicate that during the progression of LVH, both in pressure and volume overload, expression levels of endogenous inhibitors of hypertrophy are modified and that these changes may have pathophysiological significance. In particular, MCIP-1 (the endogenous calcineurin inhibitor) and VDUP-1 (the endogenous inhibitor of thioredoxin) are potential molecular switches in the progression of LV hypertrophy.

The Athlete's Heart vs. the Failing Heart: Can Signaling Explain the Two Distinct Outcomes?

“…There are clear differences in gene expression and patterns of signal transduction between concentric and eccentric hypertrophy (33,45,67); however, it is still unclear whether the different phenotypes are due to activation of distinct signaling pathways or differences in temporal and spatial activation of the same signaling proteins. Activation of ERK5 has been implicated in the development of eccentric hypertrophy, since transgenic mice with elevated ERK5 activity developed eccentric cardiac hypertrophy, which rapidly progressed to dilated cardiomyopathy and resulted in premature death (70).…”

Cardiac pressure overload hypertrophy is differentially regulated by β-adrenergic receptor subtypes

“…Sussman et al (43) showed that FK506 attenuates pressure overload hypertrophy. Another potential candidate is Txnip, an inhibitor of thioredoxin (22 A third potential candidate is S100A9, a member of the S100 family of EF-hand calcium binding proteins, implicated in cell growth mediated through NF-B (16) Another member of the calgranulin family, S100A4, is upregulated in hypertrophy (41).…”

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“…Few studies have shown no such association between the pathway of eccentric hypertrophy and activation of fetal marker genes of pathological cardiac hypertrophy. MHC (Myosin heavy chain), which is associated with increased myosin ATPase activity, enhancement of contractility and ventricular function, increased aerobic training and related exercises 39 . Chronically performed aerobic training induces cardiovascular changes; resting bradycardia has been considered to be the main effect of aerobic exercise training adaptation.…”