Ren Hao-Lin, Cai Ruiping, Xue Ruize, Zhang Yaoxia, Xu Qian, Zhang Xianyang, Cai RenZhi, Sha Wei, Schally Andrew V, Zhou Ming-Sheng
Department of Radiology, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
Science and Research Center, Shenyang Medical College, Shenyang, China.
Front Cardiovasc Med. 2023 Jan 18;10:1102525. doi: 10.3389/fcvm.2023.1102525. eCollection 2023.
Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. VC increases mortality of all-causes. VC is one of most common cardiovascular complications in type II diabetes. So far, no therapy has been proven to be effective in treatment of clinical VC. The present study investigated the therapeutic effects of MR409, an agonistic analog of growth hormone-releasing hormone (GHRH-A), on VC in diabetic db/db mice.
Diabetic mice were injected with MR409 subcutaneously every day for 8 weeks. Long-term treatment with MR409 improved serum lipid profile and endothelium-dependent relaxation to acetylcholine, and reduced vascular structural injury in diabetic mice without affecting serum growth hormone level. Echocardiography showed that calcium plaques present in heart valve of diabetic mice disappeared in diabetic mice after treatment with MR409. MR409 inhibited vascular calcium deposition associated with a marked reduction in the expressions of osteogenic-regulated alkaline phosphatase (ALP) and transcription osteogenic marker gene Runx2 in diabetic mice. MR409 also inhibited vascular reactive oxygen species (ROS) generation and upregulated the expressions of anti-calcifying protein Klotho in diabetic mice.
Our results demonstrate that GHRH-A MR409 can effectively attenuate VC and heart valve calcification, and protect against endothelial dysfunction and vascular injury in diabetic mice without significantly affecting pituitary-growth hormone axis. The mechanisms may involve upregulation of anti-calcifying protein Klotho and reduction in vascular ROS and the expression of redox sensitive osteogenic genes Runx2 and ALP. GHRH-A may represent a new pharmacological strategy for treatment of VC and diabetics associated cardiovascular complications.
血管钙化（VC）是心血管疾病的独立危险因素。VC会增加全因死亡率。VC是II型糖尿病中最常见的心血管并发症之一。迄今为止，尚无治疗方法被证明对临床VC有效。本研究调查了生长激素释放激素激动剂类似物（GHRH-A）MR409对糖尿病db/db小鼠VC的治疗效果。
糖尿病小鼠每天皮下注射MR409，持续8周。长期使用MR409可改善血清脂质谱和对乙酰胆碱的内皮依赖性舒张，并减少糖尿病小鼠的血管结构损伤，且不影响血清生长激素水平。超声心动图显示，糖尿病小鼠心脏瓣膜中的钙斑在接受MR409治疗后消失。MR409抑制血管钙沉积，同时糖尿病小鼠中成骨调节碱性磷酸酶（ALP）和转录成骨标记基因Runx2的表达显著降低。MR409还抑制糖尿病小鼠血管活性氧（ROS）的产生，并上调抗钙化蛋白Klotho的表达。
我们的结果表明，GHRH-A MR409可有效减轻VC和心脏瓣膜钙化，并预防糖尿病小鼠的内皮功能障碍和血管损伤，且不会显著影响垂体-生长激素轴。其机制可能包括上调抗钙化蛋白Klotho、减少血管ROS以及氧化还原敏感的成骨基因Runx2和ALP的表达。GHRH-A可能代表一种治疗VC和糖尿病相关心血管并发症的新药理学策略。
