Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Cardiology, The Affiliated Hospital of Yangzhou University, Yangzhou, China.
J Cell Biochem. 2019 Sep;120(9):14745-14755. doi: 10.1002/jcb.28735. Epub 2019 Apr 17.
It is known that parathyroid hormone-related peptide (PTHrP) contains a nuclear localization sequence (NLS, 87-107), which, together with its C-terminus (107-139), has been shown to positively regulate vascular smooth muscle cell (VSMCs) proliferation and vascular neointima formation, and inhibit cellular apoptosis. The role of PTHrP in ischemic cardiac diseases remains unclear. In this study, we attempted to determine whether PTHrP 87 to 139 can play a role in promoting cardiac function via enhancing angiogenesis after myocardial infarction (MI) occurred. MI was reproduced in C57BL/6 mice using a coronary artery ligation method. In total, three groups (n = 11 per group) of animals were used, and they were received either PTHrP 87 to 139 (80 µg/kg, treatment group) or saline (MI and Sham group) subcutaneously once a day for 4 weeks after MI. To measure cardiac function, an echocardiography was generated and cardiac tissue was harvested for immunohistological studies 4 weeks after operation. Our results show that, after MI, the cardiac function of the experimental mice was significantly impaired. PTHrP 87 to 139 treatment attenuated cardiac dysfunction in MI mice. Besides, as indicated by decreased heart weight/body weight and lung weight/body weight ratio, PTHrP 87 to 139 attenuated pulmonary congestion and cardiac hypertrophy. Masson staining revealed that PTHrP 87 to 139 attenuated myocardial fibrosis after MI. Also, terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling staining and the expression of cleaved caspase 3 suggested that MI-induced myocytes apotosis was inhibited by PTHrP 87 to 139. In addition to the significantly increased capillary density, PTHrP 87 to 139 treatment also induced p-Akt and several angiogenic factors. In conclusion, PTHrP 87 to 139 treatment preserved cardiac function after MI, and stimulated angiogenesis via upregulating vascular endothelial growth factor and basic fibroblast growth factor (bFGF) in infarct border zone of ischemic myocardium,. These results suggest that PTHrP 87 to 139 is of therapeutic potential for MI.
已知甲状旁腺激素相关肽（PTHrP）含有核定位序列（NLS，87-107），该序列与 C 端（107-139）一起，被证明可正向调节血管平滑肌细胞（VSMC）增殖和血管新生内膜形成，并抑制细胞凋亡。PTHrP 在缺血性心脏病中的作用尚不清楚。在这项研究中，我们试图确定 PTHrP 87-139 是否可以通过促进心肌梗死后的血管生成来发挥作用，从而改善心脏功能。使用冠状动脉结扎法在 C57BL/6 小鼠中复制 MI。总共使用了三组（每组 11 只动物）动物，它们每天皮下接受 PTHrP 87-139（80μg/kg，治疗组）或生理盐水（MI 和 Sham 组）一次，共 4 周。为了测量心功能，生成了超声心动图，并在手术后 4 周收获心脏组织进行免疫组织学研究。我们的结果表明，在 MI 后，实验小鼠的心脏功能明显受损。PTHrP 87-139 治疗可减轻 MI 小鼠的心脏功能障碍。此外，PTHrP 87-139 可降低心脏重量/体重比和肺重量/体重比，减轻 MI 引起的肺充血和心脏肥大。Masson 染色显示 PTHrP 87-139 减轻 MI 后的心肌纤维化。此外，末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记染色和 cleaved caspase 3 的表达表明，PTHrP 87-139 抑制了 MI 诱导的心肌细胞凋亡。除了毛细血管密度显著增加外，PTHrP 87-139 还通过上调血管内皮生长因子和碱性成纤维细胞生长因子（bFGF）来诱导梗死边缘区的血管生成。总之，PTHrP 87-139 治疗可改善 MI 后心脏功能，并通过上调血管内皮生长因子和碱性成纤维细胞生长因子（bFGF）来刺激血管生成。这些结果表明，PTHrP 87-139 对 MI 具有治疗潜力。
