Early sequence of cardiac adaptations and growth factor formation in pressure- and volume-overload hypertrophy

Abstract

To investigate the time sequence of cardiac growth factor formation, echocardiographic and hemodynamic measurements were performed at scheduled times, and mRNAs for angiotensinogen, prepro-endothelin-1 (ppET-1), and insulin-like growth factor I (IGF-I) were quantified with RT-PCR and localized with in situ hybridization in pigs (fluothane anesthesia) by use of pressure or volume overload (aortic banding and aorta-cava fistula, respectively). Relative peptide formation was also measured by radioimmunoassay. In pressure overload, angiotensinogen and ppET-1 mRNA overexpression on myocytes (13 times vs. sham at 3 h and 112 times at 6 h, respectively) was followed by recovery (12 h) of initially decreased (0.5-6 h) myocardial contractility. In volume overload, contractility was not decreased, the angiotensinogen gene was slightly upregulated at 6 h (6.7 times), and ppET-1 was not overexpressed. IGF-I mRNA was overexpressed on myocytes (at 24 h) in both volume and pressure overload (14 times and 37 times, respectively). In the latter setting, a second ppET-1 overexpression was detectable on myocytes at 7 days. In conclusion, acute cardiac adaptation responses involve different growth factor activation over time in pressure versus volume overload; growth factors initially support myocardial contractility and thereafter induce myocardial hypertrophy.

Acute changes of biventricular gene expression in volume and right ventricular pressure overload

“…Transgenic mice with cardiac restricted overexpression of TNF-a present progressive LV dilation (Sivasubramanian et al, 2001), and the activation of IL-6 receptor transmembranar domain gp130 in isolated neonatal rat cardiomyocytes induces sarcomere longitudinal growth (Wollert et al, 1996). RV IGF-1 overexpression in P-Band was similar to Dextran, in accordance with previous studies showing an upregulation of this gene in pressure and volume overload (Modesti et al, 2000(Modesti et al, , 2004. Given its pro-hypertrophic and anti-apoptotic actions, IGF-1 might contribute to myocardial adaptation to cardiac overload (Tanaka et al, 1998;Welch et al, 2002).…”

“…In the intact heart, acute pressure and volume overload induced different local growth factor formation (Modesti et al, 2000). This was associated with distinct hemodynamics and specific patterns of ventricular remodeling (concentric vs. eccentric hypertrophy) (Modesti et al, 2000(Modesti et al, , 2004.…”

“…This was associated with distinct hemodynamics and specific patterns of ventricular remodeling (concentric vs. eccentric hypertrophy) (Modesti et al, 2000(Modesti et al, , 2004.…”

Impaired angiotensin II–extracellular signal-regulated kinase signaling in failing human ventricular myocytes

“…In-vivo studies in pig heart showed that the early release of Ang II stored in the cardiomyocyte cytoplasm granules [3] was followed by an increase in the mRNA of preproET-1 and angiotensinogen with final ET-1 release and recovery of cardiac contractility [2]. ET-1 gene expression and peptide release, as well as the recovery of contractility, were all abrogated by AT1 receptor blockade [3].…”

“…Early growth factor formation following the application of mechanical stimuli is also mediated by Ang II as suggested by the observation that the inhibition of type I receptors for Ang II inhibited early growth factor (ET-1 and angiotensinogen) overexpression in stretched myocytes in vitro [1] and in experimental models of acute cardiac overload in vivo [2,3]. However, in patients with aortic valve disease, the progression from compensatory hypertrophy to heart failure is characterized by reduced gene expression of ventricular myocytes and cardiac formation of insulin-like growth factor-1 (IGF-I) and ET-1 [4], notwithstanding a significant increase in cardiac Ang II generation [4].…”