Different Growth Factor Activation in the Right and Left Ventricles in Experimental Volume Overload

Abstract

Abstract-Mechanical factors play a key role in activation of cardiac growth factor response in hemodynamic overload, and both cooperate in myocardial remodeling. The present study was performed to investigate whether a different growth factor response is activated in the right and left ventricles in aortocaval fistula and its effects on regional myocardial adaptation. Relations between regional growth factor expression (angiotensin II, insulin-like growth factor-I, and endothelin-1), myocyte shape changes, and collagen deposition were investigated at mRNA and peptide levels in adult pigs after the creation of an aortocaval fistula distal to the renal arteries (nϭ15) and in sham-operated animals (nϭ15). The role of angiotensin II was investigated by the administration of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. In the left ventricle, pure volume overload was accompanied by persistent increase of insulin-like growth factor-I mRNA expression, peptide concentration (2.2-fold versus sham at 3 months, PϽ0.05), and significant increase of myocyte length (ϩ29% at 3 months, PϽ0.05). Conversely, the mixed pressure-volume overload faced by the right ventricle resulted in significant regional overexpression of all growth factors investigated (angiotensin II, insulin-like growth factor-I, and endothelin-1), with corresponding increase of myocyte diameter and length and collagen deposition (ϩ117% at 3 months). Collagen accumulation in the right ventricle as well as the increase in right ventricular end-diastolic pressure at the 3-month observation were inhibited by angiotensin II antagonism. The left and right ventricles respond differently to aortocaval fistula, and local growth factor expression is closely related to the regional myocardial adaptation.

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).…”

“…P max elevation, however, was restricted to the RV, a feature also observed in the aorta-cava fistula model (Modesti et al, 2004). The selective increase of PLB and IGF-1 mRNA in the RV could indicate that, in the setting of a volume overload, some degree of concomitant pressure overload might be required for the upregulation of these genes.…”

“…This could depend on the distinct features of RV and LV, as well as on the mixed pressure -volume load faced by the RV after dextran infusion. The mixed pressure -volume load to which the RV is subjected has also been proposed to explain selective RV ppET-1 activation in chronic volume overload (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.…”

The impact of endurance exercise training on left ventricular systolic mechanics

“…The cellular response to such stimuli is an area of active interest, and the roles of gene polymorphism and growth factor activation in pathological and EET-induced cardiac hypertrophy have been recently shown (2,16,19,26,29). Furthermore, recent animal data demonstrate an upregulation of several genes with established relevance to cardiac contraction in response to ventricular pressure and volume overload (7,27,28,40). The inducibility of the sarco(endo)plasmic reticulum Ca 2ϩ -ATPase gene and the impact of its gene product on contractile function are of particular relevance (24).…”