Signaling in Myocardial Hypertrophy

Abstract

C ardiac (ventricular) hypertrophy is an important adaptive response in vivo that (at least in the shorter term) allows the organism to maintain or increase its cardiac output. Global ventricular hypertrophy is a recognized response to increased pressure or volume work (reviewed in Reference 1), with increased myofibrillogenesis and sarcomere deposition being cardinal features. Although global hypertrophy is clinically important, probably the most significant form of cardiac hypertrophy in terms of patient numbers is the localized hypertrophy of the ventricular wall that may follow loss of myocardium after a survivable myocardial infarct. In the early stages, both global and localized hypertrophy may resemble the readily reversible, nonfibrotic "physiological" hypertrophy that develops after repeated endurance exercise. In the longer term, beneficial, "compensated" hypertrophy may decay into maladaptive "decompensated" hypertrophy and heart failure (reviewed in References 2 and 3) with diminished coronary flow reserve and increased risk of lethal arrhythmias. Although some aspects of the maladapted state are probably intrinsic to the myocyte [eg, prolongation of the action potential and Ca 2ϩ transient (reviewed in References 4 and 5)], other factors (increased fibrosis and mismatch between O 2 supply and demand) are also probably involved in decompensation.The predominating view is that mammalian ventricular myocytes lose their capacity for cell division during the perinatal period and are thus terminally differentiated cells, although this is still a matter of some dispute (reviewed in References 6 and 7). In contrast, other cells in the heart (endothelial cells, fibroblasts, and smooth muscle cells) retain their mitotic capacity. Although ventricular myocytes are not the only cell type involved in the overall hypertrophic response, much of the ventricular enlargement or remodeling is attributable to their hypertrophy. The identities of signaling pathways that couple the demand for increased contractile power to increased myocyte growth and altered gene expression have been actively investigated for many years. Protein phosphorylation (catalyzed principally by Ser-/Thr-or Tyrspecific protein kinases) and phosphoprotein dephosphorylation (catalyzed by phosphoprotein phosphatases) play central roles in the regulation of many cellular events, including growth and cell division, and it is widely believed that these processes participate in myocyte hypertrophy.From the broad point of view, 2 hypotheses of hypertrophy have been proposed, which are the extrinsic and the intrinsic hypotheses. The former maintains that myocyte hypertrophy results from extracellular factors ( Table 1) that are either of a neuroendocrine origin (eg, the catecholamines) or are synthesized and released locally by the myocytes and nonmyocytes in the heart (eg, endothelin-1 [ET-1] and angiotensin II [Ang II]). The intrinsic hypothesis maintains that changes originating within the myocyte are responsible for hypertrophy. Because of its well-e...

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

“…32,33 RhoA is important for ERK1/2 activation in the mechanical stress-induced hypertrophy of cardiac myocytes. 17,34 Thus, the RhoA/Ras-ERK1/2 pathways are implicated in the signaling system that has a role in cardiac hypertrophy in response to hypertension.…”

“…During direct activation by mechanical stress, G protein-coupled receptor agonists, such as angiotensin II, endothelin-1 and phenylepherine, activate the Ras-ERK cascade via protein kinase C activation and subsequently upregulate hypertrophic gene upregulation in cardiac myocytes. 32 In addition, angiotensin II and a-adrenergic agonists activate RhoA through Ga q /Ga 11 proteins in cardiac myocytes. 17,43 We have demonstrated that the cardiac angiotensin II system is activated in SAD-operated SHRs.…”

“…Finally, several signaling pathways, such as p38 mitogen-activated protein kinase and p125 focal adhesion kinase, are implicated as mediators of stretchinduced myocyte hypertrophy. 32 Thus, it remains to be elucidated whether such pathways would contribute to the SAD-induced aggravation of cardiac hypertrophy in SHRs.…”

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

“…[17][18][19]. Evidence is emerging that the p38 MAPK pathway is an important component of the cardiac cellular stress response.…”

Reduced Transient Outward K + Current and Cardiac Hypertrophy

“…10 It is important to note that other signaling pathways such as the protein kinase C pathway or the mitogen-activated protein kinase (MAPK) cascade have also been shown to mediate the hypertrophic response in the heart. 11,12 Taken together, the majority of published evidence suggests that activation of the calcineurin signaling pathway, but not a reduction in I to density, is causally related to cardiac hypertrophy. Just when it seemed the matter was settled, Kassiri et al 13 report in this issue of Circulation Research that reduction of I tof in cultured neonatal rat ventricular myocytes causes hypertrophy via a calcineurin-dependent pathway.…”