Lysophosphatidic Acid Is Associated With Cardiac Dysfunction and Hypertrophy by Suppressing Autophagy via the LPA3/AKT/mTOR Pathway

Abstract

Background: Lysophosphatidic acid (LPA), as a phospholipid signal molecule, participates in the regulation of various biological functions. Our previous study demonstrated that LPA induces cardiomyocyte hypertrophy in vitro; however, the functional role of LPA in the post-infarct heart remains unknown. Growing evidence has demonstrated that autophagy is involved in regulation of cardiac hypertrophy. The aim of the current work was to investigate the effects of LPA on cardiac function and hypertrophy during myocardial infarction (MI) and determine the regulatory role of autophagy in LPA-induced cardiomyocyte hypertrophy.Methods: In vivo experiments were conducted in Sprague-Dawley rats subjected to MI surgery or a sham operation, and rats with MI were assigned to receive an intraperitoneal injection of LPA (1 mg/kg) or vehicle for 5 weeks. The in vitro experiments were conducted in H9C2 cardiomyoblasts.Results: LPA treatment aggravated cardiac dysfunction, increased cardiac hypertrophy, and reduced autophagy after MI in vivo. LPA suppressed autophagy activation, as indicated by a decreased LC3II-to-LC3I ratio, increased p62 expression, and reduced autophagosome formation in vitro. Rapamycin, an autophagy enhancer, attenuated LPA-induced autophagy inhibition and H9C2 cardiomyoblast hypertrophy, while autophagy inhibition with Beclin1 siRNA did not further enhance the hypertrophic response in LPA-treated cardiomyocytes. Moreover, we demonstrated that LPA suppressed autophagy through the AKT/mTOR signaling pathway because mTOR and PI3K inhibitors significantly prevented LPA-induced mTOR phosphorylation and autophagy inhibition. In addition, we found that knockdown of LPA3 alleviated LPA-mediated autophagy suppression in H9C2 cardiomyoblasts, suggesting that LPA suppresses autophagy through activation of the LPA3 and AKT/mTOR pathways.Conclusion: These findings suggest that LPA plays an important role in mediating cardiac dysfunction and hypertrophy after a MI, and that LPA suppresses autophagy through activation of the LPA3 and AKT/mTOR pathways to induce cardiomyocyte hypertrophy.

Adipose tissue-derived autotaxin causes cardiomyopathy in obese mice

“…Present findings showed blockage of autotatxin inhibited high-fat diet-induced cardiac hypertrophy, including reduction of heart weight, cell size, left ventricular dimension and left ventricular mass in obese mice. The LPA3/AKT/mTOR pathway was a potential signaling pathway in modulating cardiac hypertrophy (Yang et al 2018). Consistent with the role of autotaxin in pulmonary fibrosis (Ninou et al 2018), present study found autotaxin also participated in cardiac fibrosis.…”

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

“…Moreover, protection from cardiac hypertrophy was also associated with an attenuation of systolic dysfunction and cardiac dilatation [35]. In primary mouse cardiomyocytes, LPA administration increased proinflammatory and prohypertrophic gene expression, suggesting that LPA directly induces cardiac inflammation and hypertrophy [35], in agreement with other work demonstrating that LPA induces hypertrophic remodeling in neonatal rat ventricular cardiomyocytes [81] and H9C2 cells, and following myocardial infarction in mice in vivo [82]. Interestingly, in humans, circulating ATX levels correlated inversely with ejection fraction and positively with the hypertrophy marker, NT-proBNP, indicating that the ATX-LPA axis may also contribute to obesity-induced cardiomyopathy in humans [35].…”

Ivabradine protects rats against myocardial infarction through reinforcing autophagy via inhibiting PI3K/AKT/mTOR/p70S6K pathway

“…Intriguingly, the enhanced cardiomyocyte autophagy is reported to be mediated by the PI3K/AKT/mTOR signaling pathway [ 38 ]. Previous work has reported that PI3K/AKT pathway activation is pathogenic in cardiac dysfunction and hypertrophy [ 39 ]. Moreover, a study reported that Iva prevented cardiac hypertrophy and fibrosis via inhibiting PI3K/AKT/mTOR pathway in an established transverse aortic constriction mouse model [ 40 ].…”