Abstract
Cardiac hypertrophy is an adaptive response to cardiac overload initially but turns into a decompensated condition chronically, leading to heart failure and sudden cardiac death. The molecular mechanisms involved in cardiac hypertrophy and the signaling pathways that contribute to the switch from compensation to decompensation are not fully clear. The aim of the current study was to examine the role of PI3-kinases Class I (PI3KC1) and Class III (PI3KC3) in angiotensin (Ang) II-induced cardiac hypertrophy. The results demonstrate that treatment of cardiomyocytes with Ang II caused dose-dependent increases in autophagy, with an increasing phase followed by a decreasing phase. Ang II-induced autophagic increases were potentiated by inhibition of PI3KC1 with LY294002, but were impaired by inhibition of PI3KC3 with 3-methyladenine (3-MA). In addition, blockade of PI3KC1 significantly attenuated Ang II-induced ROS production and cardiomyocyte hypertrophy. In contrast, blockade of PI3KC3 potentiated Ang II-induced ROS production and cardiac hypertrophy. Moreover, blockade of PI3KC1 by overexpression of dominant negative p85 subunit of PI3KC1 significantly attenuated Ang II-induced cardiac hypertrophy in normotensive rats. Taken together, these results demonstrate that both PI3KC1 and PI3KC3 are involved in Ang II-induced cardiac hypertrophy by different mechanisms. Activation of PI3KC1 impairs autophagy activity, leading to accumulation of mitochondrial ROS, and, hence, cardiac hypertrophy. In contrast, activation of PI3KC3 improves autophagy activity, thereby reducing mitochondrial ROS and leads to a protective effect on Ang II-induced cardiac hypertrophy.
Highlights
Cardiac hypertrophy refers to the enlargement of cardiomyocytes with a series of physiological and pathological modifications such as heart expansion, altered gene expression, enhanced protein synthesis, and contractile machinery reorganization (Harvey and Leinwand, 2011)
The results demonstrate that chronic overexpression of Lv-dominant negative class I PI3kinase p85α subunit (DNp85) attenuates Angiotensin II (Ang II) infusion-associated activation of PI3KC1
The present study provides the first evidence that PI3KC1 contributes to Ang II-induced cardiac hypertrophy by inhibiting autophagy and increasing mitochondrial reactive oxygen species (ROS) production, and that PI3KC3 has a protective effect on Ang II-induced cardiac hypertrophy by promoting autophagy-mediated scavenging of mitochondrial ROS in cardiomyocytes. This conclusion is supported by the following evidence: 1) blockade of PI3KC1 promotes Ang II-induced autophagy; in contrast, blockade of PI3KC3 attenuates Ang II-induced autophagy; 2) blockade of PI3KC1 diminishes Ang II-induced increases in mitochondrial ROS production and hypertrophy; 3) blockade of PI3KC3 promotes the Ang II-induced increase in mitochondrial ROS production and hypertrophy; and 4) inhibition of PI3KC1 by viral vector-mediated over-expression of the dominant negative p85 subunit significantly attenuated Ang II-induced cardiac hypertrophy in the heart
Summary
Cardiac hypertrophy refers to the enlargement of cardiomyocytes with a series of physiological and pathological modifications such as heart expansion, altered gene expression, enhanced protein synthesis, and contractile machinery reorganization (Harvey and Leinwand, 2011). PI3Ks in Cardiac Hypertrophy treated, cardiac hypertrophy is a detrimental factor that would result in heart failure and sudden cardiac death, threatening the well-being of individuals and creating a tremendous burden on society as a whole. Among those physiological and pathological factors that cause cardiac hypertrophy, Angiotensin II (Ang II) stimulation plays a pivotal role (Sadoshima et al, 1993). PI3-kinases are involved in the intracellular downstream signal-transduction pathways of AT1 receptors in cardiomyocytes (Wenzel et al, 2006). The role of PI3KC1 vs. PI3KC3 in Ang IIinduced cardiac hypertrophy is still unknown
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