Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A

Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Atrial natriuretic peptide (ANP) has been postulated to exert local antihypertrophic effects in the heart. Thus, a loss of function of the ANP receptor guanylyl cyclase-A (GC-A) might contribute to the increased propensity to cardiac hypertrophy, although a causative role in vivo has not been definitively demonstrated. To test whether local ANP modulates cardiomyocyte growth, we inactivated the GC-A gene selectively in cardiomyocytes by homologous loxP/Cre-mediated recombination. Thereby we have circumvented the systemic, hypertensive phenotype associated with germline inactivation of GC-A. Mice with cardiomyocyte-restricted GC-A deletion exhibited mild cardiac hypertrophy, markedly increased mRNA expression of cardiac hypertrophy markers such as ANP (fivefold), α-skeletal actin (1.7-fold), and β-myosin heavy chain (twofold), and increased systemic circulating ANP levels. Their blood pressure was 7–10 mmHg below normal, probably because of the elevated systemic levels and endocrine actions of ANP. Furthermore, cardiac hypertrophic responses to aortic constriction were enhanced and accompanied by marked deterioration of cardiac function. This phenotype is consistent with a local function of the ANP/GC-A system to moderate the molecular program of cardiac hypertrophy

Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection*

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPARα, PPARβ/δ, and PPARγ. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPARα activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPARα and the involvement of a PPARα/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions

Relevance of nitric oxide for myocardial remodeling.

Endogenous myocardial nitric oxide (NO) may modulate the transition from adaptive to maladaptive remodeling leading to heart failure. In rodent models of pressure overload or myocardial infarction, the three NO synthase (NOS) isoforms were shown to play a neutral, protective, or even adverse role in myocardial remodeling, depending on the quantity of NO produced, the location of each NOS and their regulators, the prevailing oxidant stress and resultant NO/oxidant balance, as well as NOS coupling/dimerization. Beside neuronal NOS and--in specific conditions--inducible NOS isoforms, endothelial NOS (eNOS) exerts cardioprotective effects on pressure-overload, ischemia/reperfusion, and myocardial infarction-induced myocardial remodeling, provided the enzyme remains in a coupled state. Besides its effects on excitation-contraction coupling in response to stretch, eNOS acts as an "endogenous beta-blocker" by restoring the sympathovagal balance, opposing excessive hypertrophy as well as promoting vasodilatation and neoangiogenesis, thereby contributing to tissue repair. As eNOS was also shown to mediate the beneficial effects of cardiovascular drugs commonly used in patients with heart failure, strategies to increase its expression and/or coupled catalytic activity in the myocardium offer new therapeutic avenues for the treatment of this disease