Role of phosphoinositide signaling pathways in cardiomyocyte apoptosis and survival.

摘要

Cardiac hypertrophy has long been considered an adaptive response to increased demand placed upon the heart. However, the incidence of hypertrophy is correlated with an increased risk for the development of heart failure. As such, the molecular mechanisms that trigger the decompensation of the heart from a hypertrophied state to that of a failing phenotype are important to elucidate, either as markers for diagnostic purposes, or as drug targets to prevent the declining function of the heart. The alpha subunit of the heterotrimeric G protein, Gq, has been determined to be both necessary and sufficient to cause the development of hypertrophy in cardiomyocytes (the contractile cells of the heart). Our lab has shown that further increasing Gq signaling can lead to the development of heart failure and cardiomyocyte apoptosis. An increased incidence of apoptosis in cardiomyocytes is evident in several studies of human heart failure as well as in animal models of heart failure. Given the importance of Gq signaling in both cardiomyocyte hypertrophy and apoptosis, the work described here focused on elucidating signal transduction pathways that differed in cardiomyocytes that exhibited stable hypertrophy due to expression of Gαq (GqWT) versus those that expressed a constitutively active subunit of Gαq (Q209L) and would undergo apoptosis. The PI3-K/PDK-1/Akt pathway is defined as a major factor differentiating the two paradigms. Primary neonatal rat ventricular myocyte (NRVM) cultures expressing the Gq protein were utilized to define the activation of the PI3-K/Akt pathway by GgWT as dependent on epidermal growth factor (EGF) receptor kinase activation. This directly contrasted with less activation of the PI3-K/Akt pathway in Q209L-expressing cells, which correlated with diminished phosphatidylinositol 4,5-bisphosphate (PIP ₂) levels. In vivo experiments were carried out to examine Akt and PIP₂ regulation in Gq transgenic mice, which exhibit a heart failure phenotype in response to the stress of giving birth. These experiments confirmed that Akt phosphorylation and PIP₂ levels were diminished in Gq transgenic hearts following peripartum stress. Akt activation was, therefore, elucidated as a critical survival signal in cardiomyocytes with increased Gq activity, and a stimulatory and inhibitory mechanism were each described.