Cardiomyopathy induced by cardiac Gs alpha overexpression

Abstract

The goal of this study was to determine whether chronic endogenous sympathetic stimulation resulting from the overexpression of cardiac stimulatory G protein alpha subunit (Gs alpha) in transgenic mice (15.3 +/- 0.1 mo old) resulted in a clinical picture of cardiomyopathy. The left ventricular ejection fraction, measured by echocardiography, was reduced in older mice with Gs alpha overexpression (50.4 +/- 5.4%) compared with age-matched control mice (70.9 +/- 1.6%; P < 0.05). When ejection fractions were compared at similar heart rates, the Gs alpha mice exhibited a greater left ventricular end-diastolic dimension than control mice (4.3 +/- 0.2 vs. 3.7 +/- 0.1 mm; P < 0.05). Baseline heart rates were elevated in conscious Gs alpha mice (722 +/- 27 beats/min; n = 5) compared with control mice (656 +/- 28 beats/min; n = 5). Moreover, electrocardiographic monitoring demonstrated a high incidence of arrhythmias. Increased mortality compared with control mice (31.6 vs. 3.0%; P < 0.01) was also observed. Thus older mice with Gs alpha overexpression exhibit many of the features of dilated cardiomyopathy. This study supports the concept that chronic sympathetic stimulation over an extended period of time, i.e., over the life of an animal, is deleterious and actually may result in cardiomyopathy.

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

“…This growth response was suggested to be dependent upon increased myocyte contractile activity, and due at least in part to the release of paracrine factors by non-muscle cells (for review see Long et al, 1992). Recently, transgenic mice overexpressing Gas in the myocardium have been generated and extensively studied (Vatner et al, 2000;Iwase et al, 1996Iwase et al, , 1997. As expected, an increase in contractile sensitivity to badrenergic stimulation was evident.…”

β-adrenergic receptors signaling and heart failure in mice, rabbits and humans☆

“…They show that over-expression of Gα-s by 3-fold increased heart rate, enhanced cardiac contractility in juvenile as well as adult rabbits. The observed enhanced myocardial function in transgenic rabbits is in apparent contrast to the previously reported phenotype in transgenic mice in which the phenotype evolved from that of enhanced left ventricular function in young age to dilated cardiomyopathy at old age [15]. The findings are provocative and if substantiated, could raise considerable concerns on the utility of the mouse models of adrenergic over-stimulation in deciphering the pathogenesis of human heart failure.…”

“…At 18 months of age, approximately 2/3 exhibited cardiac hypertrophy, while transgenic rabbits older than 30 months of age exhibited a fully manifested phenotype [24]. Accordingly, the study by Nishizawa and colleagues will require follow-up studies to determine whether Gsα transgenic rabbits will develop heart failure later in life, which was also the case in the Gsα transgenic mice [15]. The Gsα transgenic mice developed cardiomyopathy at a mean age of 15 months [15].…”

“…Accordingly, the study by Nishizawa and colleagues will require follow-up studies to determine whether Gsα transgenic rabbits will develop heart failure later in life, which was also the case in the Gsα transgenic mice [15]. The Gsα transgenic mice developed cardiomyopathy at a mean age of 15 months [15]. The corresponding age in rabbits is approximately 4 years.…”

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

“…As the AC5 KO mice exhibit longevity and protection against diabetes, obesity, and cardiovascular disease (Yan et al ., 2007, 2014; Lai et al ., 2013; Ho et al ., 2015) along with enhanced exercise performance demonstrated in the current investigation, this model replicates the human paradigm of healthful aging. Conversely, enhanced β adrenergic signaling results in diminished lifespan, not only in transgenic animal models, for example, overexpression of Gsα (Iwase et al ., 1996, 1997), but also in human aging studies with increased β2 adrenergic receptor genotype, where longevity is diminished (Zhao et al ., 2012). …”