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Investigation of novel lipid-dependent cardiovascular processes
Wafa Dina
Theoretical and Translational Medicine
Dr. Kellermayer Miklós
SE Elméleti Orvostudományi Központ, Hevesy György előadóterem
2022-04-26 13:00:00
The Mechanisms of Normal and Pathologic Functions of the Circulatory System
Dr. Benyó Zoltán
Dr. Miklós Zsuzsanna
Dr. Szenci Orsolya
Dr. Tóth András
Dr. Zsembery Ákos
Dr. Cseh Domonkos
Dr. Szentandrássy Norbert
Cannabinoids and sphingosine-1-phosphate (S1P) are lipid mediators with diversified effects in the cardiovascular system. The endocannabinoid 2-arachydonoylglycerol (2-AG) has been attributed vasodilator and negative inotropic effects, while angiotensin II (Ang II) mediates vasoconstrictive and positive inotropic effects. Activation of the Ang II receptor type-1 - Gq/11 signalling pathway leads to 2-AG release and cannabinoid receptor type-1 (CB1R) activation. We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of CB1R and potential intracellular pathways in these effects. Administration of Ang II to isolated Langendorff-perfused rat hearts induced a remarkable decrease in coronary flow (CF) and a moderate decrease in cardiac function. Contrarily, administration of 2-AG and CB1R agonist WIN55,212-2 induced a significant increase in CF. Effects of Ang II were moderated in the presence of CB1R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB1R-activation, most likely due to 2-AG-release during Ang II signalling. The response to 2-AG via cardiac CB1R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction. S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury. Other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac effects of S1P during I/R and identify the signalling pathways involved. Murine hearts were exposed to intravascular S1P administration, I/R protocol, or both. S1P induced a 45% decrease of CF in WT hearts, which was diminished in S1P3R-KO but not in S1P2R-KO hearts, indicating that S1P3R mediates coronary vasoconstriction. In I/R experiments, S1P3R deficiency diminished functional recovery and increased infarct size, indicating a cardioprotective effect of S1P3R. Preischemic S1P exposure resulted in a substantial reduction of postischemic CF and cardiac performance and increased the infarcted area. These results indicate a dual role of S1P3R involving a direct protective action on the myocardium and a cardiosuppressive effect due to coronary vasoconstriction. In acute coronary syndrome when S1P is released abundantly, intravascular and myocardial S1P production may have competing influences on cardiac function via activation of S1P3Rs.