Fatty Acid Amide Hydrolase Deficiency Is Associated with Deleterious Cardiac Effects after Myocardial Ischemia and Reperfusion in Mice

Abstract

Ischemic cardiomyopathy leads to inflammation and left ventricular (LV) dysfunction. Animal studies provided evidence for cardioprotective effects of the endocannabinoid system, including cardiomyocyte adaptation, inflammation, and remodeling. Cannabinoid type-2 receptor (CB2) deficiency led to increased apoptosis and infarctions with worsened LV function in ischemic cardiomyopathy. The aim of our study was to investigate a possible cardioprotective effect of endocannabinoid anandamide (AEA) after ischemia and reperfusion (I/R). Therefore, fatty acid amide hydrolase deficient (FAAH)−/− mice were subjected to repetitive, daily, 15 min, left anterior descending artery (LAD) occlusion over 3 and 7 consecutive days. Interestingly, FAAH−/− mice showed stigmata such as enhanced inflammation, cardiomyocyte loss, stronger remodeling, and persistent scar with deteriorated LV function compared to wild-type (WT) littermates. As endocannabinoids also activate PPAR-α (peroxisome proliferator-activated receptor), PPAR-α mediated effects of AEA were eliminated with PPAR-α antagonist GW6471 i.v. in FAAH−/− mice. LV function was assessed using M-mode echocardiography. Immunohistochemical analysis revealed apoptosis, macrophage accumulation, collagen deposition, and remodeling. Hypertrophy was determined by cardiomyocyte area and heart weight/tibia length. Molecular analyses involved Taqman® RT-qPCR and immune cells were analyzed with fluorescence-activated cell sorting (FACS). Most importantly, collagen deposition was reduced to WT levels when FAAH−/− mice were treated with GW6471. Chemokine ligand-2 (CCL2) expression was significantly higher in FAAH−/− mice compared to WT, followed by higher macrophage infiltration in infarcted areas, both being reversed by GW6471 treatment. Besides restoring antioxidative properties and contractile elements, PPAR-α antagonism also reversed hypertrophy and remodeling in FAAH−/− mice. Finally, FAAH−/−-mice showed more substantial downregulation of PPAR-α compared to WT, suggesting a compensatory mechanism as endocannabinoids are also ligands for PPAR-α, and its activation causes lipotoxicity leading to cardiomyocyte apoptosis. Our study gives novel insights into the role of endocannabinoids acting via PPAR-α. We hypothesize that the increase in endocannabinoids may have partially detrimental effects on cardiomyocyte survival due to PPAR-α activation.

Restoration of adaptive cardioprotection impaired by metabolic syndrome in rats by the PPARα activation

“…Кроме того, показано, что сигналинг PGC-1 -PPARα играет важную роль в регуляции устойчивости миокарда к ишемии. Так, выявлено, что агонист PPARα клофибрат оказывал прямое антиапоптотическое действие при ишемии-реперфузии миокарда крыс с МетС [25], а антагонист PPARα GW6471 предупреждал проявление кардиопротекторного эффекта каннабиноида анандамида на модели хронической периодической ишемии миокарда (ишемической кардиомиопатии) у мышей [26]. Вместе с тем указанный сигналинг претерпевает значительные изменения как при сахарном диабете, так и при хронической гипоксии.…”

The Essence of Lipoproteins in Cardiovascular Health and Diseases Treated by Photodynamic Therapy

“…Fatty acid amide hydrolase (FAAH) hydrolyzes several very important endogenous fatty acid amides. A study by Rajlic et al showed that FAAH deficiency has negative effects on the heart after ischemia and also myocardial reperfusion in mice [82]. In addition, endocannabinoids are fatty acids and thus affect receptors that are involved in the process of fatty acid metabolism; their increase may have a negative effect on cardiomyocyte survival [82].…”

Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria

“…In FAAH-deficient mice, cardiac work after I/R deteriorated and manifested with an increase in fibrosis, left ventricle and cardiomyocyte hypertrophy, wall thickening and a decrease in fractional shortening ( Rajlic et al, 2022 ), Table 4 ]. These detrimental cardiac effects evoked by enhanced endocannabinoid tone were reversed by the peroxisome proliferator-activated receptor α (PPARα) antagonist GW6471 suggesting the involvement of PPARα receptors [( Rajlic et al, 2022 ) Table 4 ].…”

“…Furthermore, most experiments were conducted on healthy rodents and cannabinoids were administered once only. Therefore, we were unable to give details to (1) the best timing of (endo)cannabinoid administration, i.e., before, during or after ischemia (from the clinical perspective, the best time for treatment is after ischemia or AMI, but this time of administration had been chosen by few of the studies only); (2) the effect of (endo)cannabinoids in animals with comorbidities and under chronic drug treatment; (3) the detrimental effects of the blockade of endocannabinoid degradation since only few studies of that type had been performed ( Schloss et al, 2019 ; Rajlic et al, 2022 ). Moreover, the cardioprotective effects of (endo)cannabinoids in the human heart had been examined in few studies only ( Table 1 ).…”