Experimental Activation of Endocannabinoid System Reveals Antilipotoxic Effects on Cardiac Myocytes.

Hypertension coincides with myocardial alternations in lipid (including sphingolipids) and glucose metabolism. The latest data indicate that accumulation of metabolically active lipids, especially ceramide (CER) and diacylglycerol (DAG) significantly influences intracellular signaling pathways along with inducing insulin resistance. Since, it was demonstrated that the endocannabinoid system (ECS) affects myocardial metabolism it seems to be a relevant tool in alleviating metabolic disturbances within the cardiac muscle due to hypertension. All designed experiments were conducted on the animal model of primary hypertension, i.e., spontaneously hypertensive rat (SHR) with chronic ECS activation by injections of fatty acid amide hydrolase (FAAH) inhibitor-URB597. Lipid analyses were performed using chromatography techniques (gas liquid, thin layer, and high performance liquid chromatography). Colorimetric and immunoenzymatic testes were applied in order to determine plasma concentrations of insulin and glucose. Total myocardial expression of selected proteins was measured by Western blotting and/or immunohistochemistry methods. SHRs exhibited significantly intensified myocardial de novo pathway of CER synthesis as well as DAG accumulation compared to the control Wistar Kyoto rats. Besides, intramyocardial level of potentially cardioprotective sphingolipid, i.e., sphingosine-1-phosphate was considerably decreased in SHRs, whereas URB597 treatment restored the level of this derivative. Unexpectedly, ECS upregulation protected overloaded cardiac muscle against CER and DAG accumulation. Moreover, chronic URB597 treatment improved intramyocardial insulin signaling pathways in both normotensive and hypertensive conditions. It seems that the enhanced ECS triggers protective mechanisms in the heart due to decreasing the level of lipid mediators of insulin resistance.

How Hypertension Affects Heart Metabolism.

Hypertension is one of the most frequently observed cardiovascular diseases, which precedes heart failure in 75% of its cases. It is well-established that hypertensive patients have whole body metabolic complications such as hyperlipidemia, hyperglycemia, decreased insulin sensitivity or diabetes mellitus. Since myocardial metabolism is strictly dependent on hormonal status as well as substrate milieu, the above mentioned disturbances may affect energy generation status in the heart. Interestingly, it was found that hypertension induces a shift in substrate preference toward increased glucose utilization in cardiac muscle, prior to structural changes development. The present work reports advances in the aspect of heart metabolism under high blood pressure conditions, including human and the most common animal models of hypertension.