l‐α‐Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK‐dependent pathway

Abstract

The phospholipid l‐α‐lysophosphatidylinositol ( LPI ), an endogenous ligand for GPR 55, is elevated in patients with acute coronary syndrome, and a GPR 55 antagonist cannabidiol ( CBD ) reduces experimental ischemia/reperfusion (I/R) injury. While LPI activates multiple signaling pathways, little is known about which ones are important in cardiomyocytes. In this study we explored whether activation of the Rho kinase/ ROCK /p38 MAPK pathway is responsible for LPI ‐induced extension of I/R injury. Using a high‐throughput screening method (dynamic mass redistribution; DMR ), mouse‐ and human‐induced pluripotent stem cell ( iPSC ) cardiomyocytes exposed to LPI were shown to exhibit a rapid, sustained, and concentration‐dependent (1 nmol L −1 ‐30 μmol L −1 ) cellular response. Y‐27632 ( ROCK inhibitor; 10 & 50 μmol L −1 ) and CBD (1 μmol L −1 ) both abolished the DMR response to LPI (10 μmol L −1 ). In murine iPSC cardiomyocytes, LPI ‐induced ROCK and p38 MAPK phosphorylation, both of which were prevented by Y‐27632 and CBD , but did not induce JNK activation or cleavage of caspase‐3. In hearts isolated from wild type ( WT ) mice subjected to 30 minutes global I/R, LPI (10 μmol L −1 ) administered via the coronary circulation increased infarct size when applied prior to ischemia onset, but not when given at the time of reperfusion. The exacerbation of tissue injury by LPI was not seen in hearts from GPR 55 −/− mice or in the presence of Y‐27632, confirming that injury is mediated via the GPR 55/ ROCK /p38 MAPK pathway. These findings suggest that raised levels of LPI in the vicinity of a developing infarct may worsen the outcome of AMI.

Atheroma-Specific Lipids in ldlr–/– and apoe–/– Mice Using 2D and 3D Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging

“…Moreover, high levels of LPI have been related with a poor outcome in acute myocardial infarction. 28 Nevertheless, the specific role of this LPI in necrosis still has to be explored with other techniques.…”

Therapeutic Applications of Cannabinoids in Cardiomyopathy and Heart Failure

“…The results indicate that the inhibition of Ca 2+ signaling underlies the negative inotropic effects of CBD in myocytes, presenting a reduction in maximal shortening amplitudes with no alteration of the time course of contraction. However, Robertson-Gray et al [23] observed a cardioprotective effect of CBD against l-α-lysophosphatidylinositol (LPI), an endogenous ligand of G protein-coupled receptor 55 (GPR55), a putative cannabinoid receptor, which is also elevated in patients with the coronary syndrome. The injury was decreased by CBD acting as an antagonist of the GPR55 receptor.…”

“…In Ca 2+ homeostasis, CBD causes the inhibition of L-type Ca 2+ channels, impeding the internalization of additional Ca 2+ from the interstitial medium. When coupled with a reduction in the IP 3 -mediated release of Ca 2+ from the sarcoplasmic reticulum, it results in difficulty depolarizing the cellular membrane, restraining the triggering of the myocyte action potential [23]. In pathological conditions involving high extracellular K + , CBD can modulate the activation of the Na + /Ca 2+ exchanger (NCX) to release additional Ca 2+ from the cytosol into the extracellular space [33].…”

Mechanisms for the Risk of Acute Coronary Syndrome and Arrhythmia Associated With Phytogenic and Synthetic Cannabinoid Use

“…77 The theoretical contribution of these noncannabinoid GPRs to the genesis of cannabinoid-induced cardiac arrhythmias and ACS may be from alteration of endothelial vasoregulation and membrane cation currents of the cardiac conduction system. 78…”