Bin Dayel Anfal F, Alonazi Asma S, Alrasheed Nawal M, Alamin Maha A, Sarawi Wedad S, Alharbi Abeer O, Alabbad Nahla'a A, Albuaijan Danah A, Alassiri Dareen N, Aljarbua Alanoud F, Almusaytir Fatimah K, Alrasheed Nouf M
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
J Pharm Pharmacol. 2024 Jan 6;76(1):64-73. doi: 10.1093/jpp/rgad111.
Diabetic cardiomyopathy is a known complication of diabetes mellitus. Herein, we aimed to determine whether glycemic control mediated by sitagliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate diabetic myocardial abnormalities by modulating TGF-β signaling via the SMAD and integrin-linked kinase (ILK) pathways.
Four groups of male Wistar albino rats were used, with six rats in each group. Two nondiabetic and two diabetic (produced by a single intraperitoneal dose of streptozotocin (55 mg/kg)) groups were administered either normal saline or sitagliptin (100 mg/kg) orally for 6 weeks. Subsequently, HW/BW ratios and cardiac enzymes were assessed, along with a histological examination of cardiac tissues. Levels of TGF-β, collagen I, p-SMAD2/3, TNF-α, MMP-9, and ILK were detected.
Compared with the diabetic control group, sitagliptin-treated diabetic rats exhibited considerably reduced HW/BW ratios and troponin I and creatine kinase-MB levels, with improvements in histopathological changes in cardiac tissues. TGF-β, collagen I, p-SMAD2/3, TNF-α, and MMP-9 levels were significantly decreased in the sitagliptin-treated diabetic group, whereas ILK was elevated following sitagliptin treatment.
Sitagliptin could afford cardioprotective effects for the first time by altering ILK-associated TGF-β/SMAD signaling pathways. Thus, sitagliptin may be a promising therapeutic target for the prevention of diabetic cardiomyopathy.
糖尿病性心肌病是糖尿病已知的并发症。在此，我们旨在确定二肽基肽酶-4抑制剂西他列汀介导的血糖控制是否能通过SMAD和整合素连接激酶（ILK）途径调节转化生长因子-β（TGF-β）信号传导，从而改善糖尿病心肌异常。
使用四组雄性Wistar白化大鼠，每组六只。两组非糖尿病大鼠和两组糖尿病大鼠（通过单次腹腔注射链脲佐菌素（55mg/kg）诱导产生）分别口服生理盐水或西他列汀（100mg/kg），持续6周。随后，评估心脏重量/体重（HW/BW）比值和心肌酶，并对心脏组织进行组织学检查。检测TGF-β、I型胶原、磷酸化SMAD2/3、肿瘤坏死因子-α（TNF-α）、基质金属蛋白酶-9（MMP-9）和ILK的水平。
与糖尿病对照组相比，西他列汀治疗的糖尿病大鼠HW/BW比值以及肌钙蛋白I和肌酸激酶同工酶MB水平显著降低，心脏组织的组织病理学变化有所改善。西他列汀治疗的糖尿病组中，TGF-β、I型胶原、磷酸化SMAD2/3、TNF-α和MMP-9水平显著降低，而西他列汀治疗后ILK水平升高。
西他列汀首次通过改变与ILK相关的TGF-β/SMAD信号通路发挥心脏保护作用。因此，西他列汀可能是预防糖尿病性心肌病的一个有前景的治疗靶点。
