Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway

Abstract

Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinasedependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussed.Growth of the heart during embryonic development occurs primarily through proliferation of cardiac myocytes. However, cardiac myocytes withdraw from the cell cycle soon after birth, and subsequent growth of the heart during postnatal development is achieved predominantly through hypertrophy rather than hyperplasia of individual myocytes (Pasumarthi and Field 2002;Olson and Schneider 2003). In fact, there is almost a threefold increase in cardiac myocyte diameter in humans during development from infants to adults (Hudlicka and Brown 1996). Cardiac growth during normal postnatal development or the hypertrophy observed in trained athletes is referred to as "physiological," and it is characterized by normal or enhanced contractile function and normal architecture and organization of cardiac structure (Richey and Brown 1998). On the other hand, cardiac hypertrophy is also observed in patients with pathological conditions such as hypertension, myocardial infarction, and valvular heart diseases. This type of cardiac growth is called "pathological" hypertrophy, and is frequently associated with contractile dysfunction, interstitial fibrosis, and re-expression of fetal-type cardiac genes such as atrial natriuretic peptide and ␤-myosin heavy chain (Molkentin and Dorn 2001;Frey and Olson 2003). These data indicate that pathological cardiac hypertrophy is morphologically and molecularly distinct from physiological cardiac hypertrophy. The pathological form of cardiac hypertrophy is initially recognized as an adaptive response to increased external load, because increased wall stress induced by overload is attenuated by the increase in wall thickness. However, increased cardiac mass is clinically associated with increased morbidity and mortality (Levy et al. 1990), and a sustained overload eventually leads to contractile dysfunction and heart failure through poorly understood mechanisms (Molkentin and Dorn 2001;Frey and Olson 2003). In addition, hypertrophy of individual myocyte is a common feature of failing myocardium (Gerdes et al. 1992). Thus, pathological ...

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

“…In general, angiogenesis has been considered necessary to support ongoing hypertrophy induced by a hemodynamic stimulus such as pressure overload. Inhibition of angiogenic response has been demonstrated to lead to a rapid progression from compensated hypertrophy to heart failure (7,(20)(21)(22). In this study, we demonstrate that angiogenesis can induce myocardial hypertrophy even in the absence of a hemodynamic stimulus.…”

Adiponectin protects against the development of systolic dysfunction following myocardial infarction

“…The ratio of myocyte size to capillary density has been shown to be a critical determinant in the transition between compensatory hypertrophy and heart failure in experimental animals [34][35][36]. Furthermore, analyses of autopsy samples reveals that patients with end-stage heart failure, due to ischemic, inflammatory or idiopathic dilated cardiomyopathy, exhibit diminished densities and irregular patterns of myocardial capillaries [37] Indeed, agents that promote angiogenesis have been shown to be beneficial for cardiac remodeling after chronic myocardial ischemia [38][39][40].…”

VEGF-mediated PI3K class IA and PKC signaling in cardiomyogenesis and vasculogenesis of mouse embryonic stem cells

“…Akt-dependent signaling pathways are known to be involved in the regulation of cardiac growth, contractile function, and coronary angiogenesis (Shiojima and Walsh, 2006;Fujio et al, 2000;Matsui et al, 1999), suggesting a possible role in pathways regulating cardiovascular differentiation from cardiovascular progenitor cells in the heart. Our assumption was firstly supported by experiments demonstrating that silencing of the PI3K catalytic subunits p110a and p110 abolished VEGFmediated Akt and PDK1 phosphorylation and likewise blunted PKC activation, which is presumably mediated via the PDK1 pathway.…”