Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response

Abstract

Studies from both in vivo and in vitro model systems have provided an initial skeleton of the potential signaling pathways that might regulate cardiac genes during growth and hypertrophy. One of the first detectable changes in cardiac gene expression is the activation of a program of immediate early gene expression, which is distinct for the hypertrophic response, and is conserved in multiple models of both in vivo and in vitro hypertrophy. Diverse and distinct hormonal stimuli have been documented to activate several features of the hypertrophic response, including several autocrine and paracrine factors. Although the signaling mechanisms that link these factors with the activation of cardiac gene expression are unclear, recent studies suggest that the activation of protein kinase C may represent one of the most proximal common events in this signaling cascade. The activation of cardiac target genes induces a program of embryonic gene expression, including the atrial natriuretic factor (ANF) gene. The cis sequences that mediate cardiac-specific and inducible expression of an embryonic marker gene (ANF) can be segregated by studies in both cultured cell models and in vivo models of hypertrophy in transgenic mice, suggesting that specific sets of regulatory elements may exist for inducible expression of this class of cardiac gene responses. However, the induction of a constitutively expressed contractile protein gene (MLC-2) is mediated by a set of conserved elements that regulate both cardiac-specific and inducible expression. Finally, a subset of cardiac muscle genes appears to be noninducible during in vivo or in vitro hypertrophy in myocardial cells, demonstrating specificity of transcriptional activation during the hypertrophic process. The development of a bona fide in vivo pressure overload model of hypertrophy in a small animal model that can be genetically manipulated, such as the in vivo murine model recently described, should allow a rigorous analysis of the role of these specific signaling mechanisms in the activation of the responses of cardiac genes during the hypertrophic process in vivo.

Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation

“…Induction of hypertrophy in neonatal cardiac myocytes using a variety of model systems and hypertrophic stimuli is associ- (25)(26)(27)(28). Contractile stimulation of cardiac myocytes in serum-free culture results in cardiac growth and increased myofibrillar organization in vitro, suggesting that the alterations in myofibrillar content may occur by an autocrine pathway (29,30).…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…The increase in HW/ BW ratio in post-MI rats was consistent with the presence of enlarged cardiomyocytes (cross-sectional width 32.1±0.8µm to compare with sham: 23.5 ± 0.6 µm; P<0.05, Fig.3b), next to interstitial collagen deposits in the noninfarcted LV. Fibrosis (Fig.3c) and re-expression of fetal atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-ß isoform genes (Fig.3d) attested to pathological hypertrophy [36][37][38][39]. One-month NAC treatment did not lessen hypertrophy (Fig.3a).…”

Activation of c-Jun N-Terminal Kinases and p38-Mitogen-activated Protein Kinases in Human Heart Failure Secondary to Ischaemic Heart Disease

“…21 ET-1, PE, and PMA are powerful hypertrophic agonists in cultured cardiac myocytes. It was suggested in 1993 that activation of the ERK cascade by these agonists may mediate the hypertrophic response.…”

“…The CRE-like and serum response element consensus elements may be involved in the upregulation of c-jun and c-fos expression seen in cultured cardiac myocytes under a variety of conditions (eg, the responses to hypertrophic agonists, stretch, and metabolic and ischemia/reperfusion stresses). [21][22][23][24][25] c-Jun also forms heterodimers with c-Fos to transactivate at activator protein-1 (AP-1)-like sites, 26 which are present in many gene promoter regions.…”