Cannabinoid 2 Receptor Activation Protects against Diabetic Cardiomyopathy through Inhibition of AGE/RAGE-Induced Oxidative Stress, Fibrosis, and Inflammasome Activation

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 391; no. 2; pp. 241 - 257
• Main Authors: Hashiesh, Hebaallah Mamdouh, Azimullah, Sheikh, Nagoor Meeran, Mohamed Fizur, Saraswathiamma, Dhanya, Arunachalam, Seenipandi, Jha, Niraj Kumar, Sadek, Bassem, Adeghate, Ernest, Sethi, Gautam, Albawardi, Alia, Al Marzooqi, Saeeda, Ojha, Shreesh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024
• Subjects: advanced glycation end product; AGE; AKT; Animals; apoptosis-associated speck-like protein containing a CARD; area under the curve; ASC; AUC; BCP; body weight; cannabinoid 1 receptor; cannabinoid 2 receptor; CAT; catalase; CB1R; CB2R; DCM; Diabetic Cardiomyopathies - drug therapy; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - pathology; Diabetic Cardiomyopathies - prevention & control; diabetic cardiomyopathy; EndMT; endothelial-to-mesenchymal transition; Fibrosis; Glycation End Products, Advanced - metabolism; heart weight; heme oxygenase-1; HFD; high-fat diet; HO-1; HOMA-IR; homeostatic model assessment of insulin resistance; IL-18; IL-1β; Inflammasomes - metabolism; interleukin 18; interleukin-1β; Keap1; kelch-like ECH-associated protein 1; Male; matrix metalloproteinase; Mice; Mice, Inbred C57BL; MMP; NADPH oxidase 4; NLRP3; NOX4; NrF2; nuclear factor erythroid 2–related factor 2; nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3; OGTT; oral glucose tolerance test; Oxidative Stress - drug effects; phosphoinositide 3-kinase; PI3K; protein kinase B; RAGE; reactive oxygen species; Receptor for Advanced Glycation End Products - metabolism; receptor of advanced glycation end product; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - metabolism; ROS; sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a; SERCA2a; Signal Transduction - drug effects; Smad; SOD; superoxide dismutase; suppressor of mothers against decapentaplegic; TGF-β; TnI; transforming growth factor-β; troponin I; α-SMA; α-smooth muscle actin; β-caryophyllene; HFD; HO-1; SERCA2a; AUC; HW; α-SMA; ASC; PI3K; BW; NLRP3; TGF-β; EndMT; AGE; CB2R; SOD; AKT; RAGE; IL-1β; BCP; TnI; DCM; HOMA-IR; MMP; NrF2; IL-18; CAT; ROS; Keap1; NOX4; Smad; OGTT; CB1R
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.123.002037

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)–receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2–related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms. BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2β and TGF-β/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy. ▪