Experimental Activation of Endocannabinoid System Reveals Antilipotoxic Effects on Cardiac Myocytes.
Ewa Harasim-SymborAgnieszka Polak-IwaniukKarolina Konstantynowicz-NowickaPatrycja BielawiecBarbara MalinowskaIrena KasackaAdrian ChabowskiPublished in: Molecules (Basel, Switzerland) (2020)
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.
Keyphrases
- left ventricular
- blood pressure
- fatty acid
- insulin resistance
- high performance liquid chromatography
- type diabetes
- signaling pathway
- skeletal muscle
- mass spectrometry
- poor prognosis
- tandem mass spectrometry
- heart failure
- metabolic syndrome
- glycemic control
- adipose tissue
- high fat diet
- simultaneous determination
- cell proliferation
- oxidative stress
- solid phase extraction
- polycystic ovary syndrome
- machine learning
- induced apoptosis
- nitric oxide
- fluorescent probe
- liquid chromatography
- binding protein
- endoplasmic reticulum stress
- hydrogen peroxide
- room temperature
- replacement therapy
- reactive oxygen species