Downregulation of PTEN Promotes Autophagy via Concurrent Reduction in Apoptosis in Cardiac Hypertrophy in PPAR α−/− Mice

Abstract

Cardiac hypertrophy is characterized by an increase in the size of the cardiomyocytes which is initially triggered as an adaptive response but ultimately becomes maladaptive with chronic exposure to different hypertrophic stimuli. Prolonged cardiac hypertrophy is often associated with mitochondrial dysfunctions and cardiomyocyte cell death. Peroxisome proliferator activated receptor alpha (PPAR α), which is critical for mitochondrial biogenesis and fatty acid oxidation, is down regulated in hypertrophied cardiomyocytes. Yet, the role of PPAR α in cardiomyocyte death is largely unknown. To assess the role of PPAR α in chronic hypertrophy, isoproterenol, a β-adrenergic receptor agonist was administered in PPAR α knock out (PPAR α−/−) mice for 2 weeks and hypertrophy associated changes in cardiac tissues were observed. Echocardiographic analysis ensured the development of cardiac hypertrophy and compromised hemodynamics in PPAR α−/− mice. Proteomic analysis using high resolution mass spectrometer identified about 1,200 proteins enriched in heart tissue. Proteins were classified according to biological pathway and molecular functions. We observed an unexpected down regulation of apoptotic markers, Annexin V and p53 in hypertrophied heart tissue. Further validation revealed a significant down regulation of apoptosis regulator, PTEN, along with other apoptosis markers like p53, Caspase 9 and c-PARP. The autophagy markers Atg3, Atg5, Atg7, p62, Beclin1 and LC3 A/B were up regulated in PPAR α−/− mice indicating an increase in autophagy. Similar observations were made in a high cholesterol diet fed PPAR α−/−mice. The results were further validated in vitro using NRVMs and H9C2 cell line by blocking PPAR α that resulted in enhanced autophagosome formation upon hypertrophic stimulation. The results demonstrate that in the absence of PPAR α apoptotic pathway is inhibited while autophagy is enhanced. The data suggest that PPAR α signaling might act as a molecular switch between apoptosis and autophagy thereby playing a critical role in adaptive process in cardiac hypertrophy.

Metoprolol Mitigates Ischemic Heart Remodeling and Fibrosis by Increasing the Expression of AKAP5 in Ischemic Heart

“…In arrhythmia, AKAP150 acts in two ways: it intensifies arrhythmia caused by calcium channel-related gene mutation [13], and it may have a therapeutic effect on arrhythmia caused by potassium channel-related gene mutation [14,15]. β1-adrenergic receptor (β-AR) stimulation in vitro and in vivo increased the expression and activity of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in cardiac myocytes [16]; it also induced cardiomyocyte apoptosis [7,17,18]. In addition, β1-AR-mediated increase in cyclic adenosine monophosphate was greater in AKAP5 null myocytes [19].…”

“…β 1-adrenergic receptor ( β -AR) stimulation in vitro and in vivo increased the expression and activity of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in cardiac myocytes [ 16 ]; it also induced cardiomyocyte apoptosis [ 7 , 17 , 18 ]. In addition, β 1-AR–mediated increase in cyclic adenosine monophosphate was greater in AKAP5 null myocytes [ 19 ].…”

Transcriptome analysis of the potential mechanisms regulating autophagy in matrine- treated IMCD3 cells

“…In contrast, the down-regulated genes were enriched in the cholesterol metabolism, in uenza A, measles and NOD-like receptor signaling pathway, among which NOD-like receptor signaling has a role in regulating autophagy 12 . As for the 0.4 mg/mL matrine treated group, we found that, compared with the control group, the up-regulated DEGs are enriched in signal transduction, including adrenergic signaling in cardiomyocytes 13,14 , Hippo signaling pathway 15,16 , Apelin signaling pathway 17 and calcium signaling pathway 18,19 , and these are closely related to autophagy. The down-regulated genes were also enriched in signal transduction, including the NOD-like receptor signaling pathway, Il-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and Chemokine and JAK-STAT signaling pathways, among which the NOD-like receptor signaling pathway, IL-17 signaling pathway 20 , AGE-RAGE signaling pathway 21 and JAK-STAT signaling pathway 22 regulate autophagy (Fig.…”

“…It has been demonstrated that all of these signaling pathways are important in the process of autophagy 33,34 . Alterations in the signals, will drive autophagy-related diseases such as heart disease 13 , neurodegenerative diseases 19 and cancer 15,17 . Furthermore, most of the above signaling pathways are important in the development of PKDs.…”

Novel pentacyclic derivatives and benzylidenes of the progesterone series cause anti-estrogenic and antiproliferative effects and induce apoptosis in breast cancer cells

“…Tamoxifen treatment resulted in a partial increase in ERα expression, which may be attributed to the stabilization of inactivated cytoplasmic ERα [ 53 , 54 ]. Moreover, all three compounds led to the cleavage of PARP (116 kDa) and the formation of an 89-kDA PARP fragment, which is a key marker of apoptotic cell death [ 55 – 57 ]. The effect grew with the increase of the compound concentration from 5 to 15 µM.…”