Transgenic Gαq overexpression induces cardiac contractile failure in mice

Abstract

The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of G␣q-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type G␣q in the heart using the ␣-myosin heavy chain promoter. Two-fold overexpression of G␣q showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor (Ϸ55-fold), ␤-myosin heavy chain (Ϸ8-fold), and ␣-skeletal actin (Ϸ8-fold) expression, and decreased (Ϸ3-fold) ␤-adrenergic receptor-stimulated adenylyl cyclase activity. All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure. Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 ؎ 2% vs. 41 ؎ 3%), dP͞dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the ␤-adrenergic agonist dobutamine. At higher levels of G␣q overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death. The element within the pathway that appeared to be critical for these events was activation of protein kinase C. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated. The G␣q overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

“…On the other hand, hearts in the Kidney KOs appeared virtually normal, indicating that vascular injury and fibrosis in the heart were also consequences of elevated blood pressure rather than local actions of cardiac AT 1 receptors. Cardiac hypertrophy is associated with characteristic alterations in gene expression, including up-regulation of ANP and BNP (31,32), and recapitulation of fetal patterns for expression of myosin heavy chains (33,34). It has been suggested that activation of AT 1 receptors in cardiomyocytes may be sufficient to trigger this transcription profile (34,35).…”

“…Cardiac hypertrophy is associated with characteristic alterations in gene expression, including up-regulation of ANP and BNP (31,32), and recapitulation of fetal patterns for expression of myosin heavy chains (33,34). It has been suggested that activation of AT 1 receptors in cardiomyocytes may be sufficient to trigger this transcription profile (34,35). However, as we observed with cardiac hypertrophy and pathology, activation of AT 1 receptors in the heart is not responsible for characteristic gene expression patterns associated with Ang II infusion; these are also triggered by elevated blood pressure.…”

“…Although our evaluations of heart weight and histology indicate a dominant effect of blood pressure on cardiac pathology, we considered the possibility that these assessments might not be sufficiently sensitive to detect cellular actions of AT 1 receptors in cardiac myocytes. During hypertrophic cardiac remodeling, gene expression in myocardium undergoes characteristic alterations, including enhanced expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), along with recapitulation of fetal gene expression patterns for myosin heavy chains (MHC) characterized by a down-regulation of ␣-MHC and up-regulation of the ␤-MHC isoform (31)(32)(33)(34). Previous studies have suggested that Ang II may stimulate these processes (35,36).…”

Rescue of Contractile Parameters and Myocyte Hypertrophy in Calsequestrin Overexpressing Myocardium by Phospholamban Ablation

“…In Vivo and ex Vivo Left Ventricular Function-Left ventricular contractile parameters were determined in closed-chest anesthetized mice using a 1.4-French scale Millar MIKRO-TIP catheter, as previously described (25). Contractile parameters of isolated hearts were also determined in Langendorff mode at 37°C with a constant perfusion pressure of 50 mm Hg, as described previously (23).…”

G-proteins in growth and apoptosis: lessons from the heart

“…These paradigms were recapitulated in transgenic mice generated in Dorn's laboratory. Initial studies with these transgenic mice showed that a modest (four-fold) overexpression of Gaq in the myocardium lead to development of a stable form of cardiac hypertrophy (D'Angelo et al, 1997). However, when these mice were subjected to the neurohumoral or hemodynamic stresses associated with parturition (Adams et al, 1998b) or to chronic pressure overload Adams et al, manuscript in preparation) cardiac failure rapidly developed in association with increased cardiomyocyte apoptosis.…”