Mamdouh Hashiesh Hebaallah, Sheikh Azimullah, Meeran Mohamed Fizur Nagoor, Saraswathiamma Dhanya, Jha Niraj Kumar, Sadek Bassem, Adeghate Ernest, Tariq Saeed, Al Marzooqi Saeeda, Ojha Shreesh
Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box: 15551, Al Ain, United Arab Emirates.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt.
ACS Pharmacol Transl Sci. 2023 Jul 26;6(8):1129-1142. doi: 10.1021/acsptsci.3c00027. eCollection 2023 Aug 11.
Diabetes mellitus (DM) and its associated complications are considered one of the major health risks globally. Among numerous complications, diabetic cardiomyopathy (DCM) is characterized by increased accumulation of lipids and reduced glucose utilization following abnormal lipid metabolism in the myocardium along with oxidative stress, myocardial fibrosis, and inflammation that eventually result in cardiac dysfunction. The abnormal metabolism of lipids plays a fundamental role in cardiac lipotoxicity following the occurrence and development of DCM. Recently, it has been revealed that cannabinoid type-2 (CB2) receptors, an essential component of the endocannabinoid system, play a crucial role in the pathogenesis of obesity, hyperlipidemia, and DM. Provided the role of CB2R in regulating the glucolipid metabolic dysfunction and its antioxidant as well as anti-inflammatory activities, we carried out the current study to investigate the protective effects of a selective CB2R agonist, β-caryophyllene (BCP), a natural dietary cannabinoid in the murine model of DCM and elucidated the underlying pharmacological and molecular mechanisms. Mice were fed a high-fat diet for 4 weeks followed by a single intraperitoneal injection of streptozotocin (100 mg/kg) to induce the model of DCM. BCP (50 mg/kg body weight) was given orally for 12 weeks. AM630, a CB2R antagonist, was given 30 min before BCP treatment to demonstrate the CB2R-dependent mechanism of BCP. DCM mice exhibited hyperglycemia, increased serum lactate dehydrogenase, impaired cardiac function, and hypertrophy. In addition, DCM mice showed alternations in serum lipids and increased oxidative stress concomitant to reduced antioxidant defenses and enhanced cardiac lipid accumulation in the diabetic heart. DCM mice also exhibited activation of TLR4/NF-κB/MAPK signaling and triggered the production of inflammatory cytokines and inflammatory enzyme mediators. However, treatment with BCP exerted remarkable protective effects by favorable modulation of the biochemical and molecular parameters, which were altered in DCM mice. Interestingly, pretreatment with AM630 abrogated the protective effects of BCP in DCM mice. Taken together, the findings of the present study demonstrate that BCP possesses the capability to mitigate the progression of DCM by inhibition of lipotoxicity-mediated cardiac oxidative stress and inflammation and favorable modulation of TLR4/NF-κB/MAPK signaling pathways mediating the CB2R-dependent mechanism.
糖尿病及其相关并发症被认为是全球主要的健康风险之一。在众多并发症中，糖尿病性心肌病（DCM）的特征是心肌脂质代谢异常后脂质积累增加和葡萄糖利用减少，同时伴有氧化应激、心肌纤维化和炎症，最终导致心脏功能障碍。脂质代谢异常在DCM发生和发展后的心脏脂毒性中起重要作用。最近，有研究表明，大麻素2型（CB2）受体作为内源性大麻素系统的重要组成部分，在肥胖、高脂血症和糖尿病的发病机制中起关键作用。鉴于CB2R在调节糖脂代谢功能障碍及其抗氧化和抗炎活性方面的作用，我们开展了本研究，以探讨选择性CB2R激动剂β-石竹烯（BCP，一种天然膳食大麻素）在DCM小鼠模型中的保护作用，并阐明其潜在的药理和分子机制。小鼠先喂高脂饮食4周，然后单次腹腔注射链脲佐菌素（100 mg/kg）以诱导DCM模型。口服给予BCP（50 mg/kg体重），持续12周。在BCP治疗前30分钟给予CB2R拮抗剂AM630，以证明BCP的CB2R依赖性机制。DCM小鼠表现出高血糖、血清乳酸脱氢酶升高、心脏功能受损和心肌肥大。此外，DCM小鼠血清脂质发生改变，氧化应激增加，同时抗氧化防御能力降低，糖尿病心脏中的心脏脂质积累增加。DCM小鼠还表现出TLR4/NF-κB/MAPK信号通路的激活，并引发炎症细胞因子和炎症酶介质的产生。然而，BCP治疗通过对DCM小鼠中改变的生化和分子参数进行有利调节而发挥了显著的保护作用。有趣的是，AM630预处理消除了BCP对DCM小鼠的保护作用。综上所述，本研究结果表明，BCP具有通过抑制脂毒性介导的心脏氧化应激和炎症以及对介导CB2R依赖性机制的TLR4/NF-κB/MAPK信号通路进行有利调节来减轻DCM进展的能力。
