Divisions of Cardiology (D.K., P.C.) and Rheumatology (C.R., S.H.), Department of Medicine, Medical University of South Carolina, Charleston, Charleston, South Carolina
Divisions of Cardiology (D.K., P.C.) and Rheumatology (C.R., S.H.), Department of Medicine, Medical University of South Carolina, Charleston, Charleston, South Carolina.
J Pharmacol Exp Ther. 2021 Jul;378(1):1-9. doi: 10.1124/jpet.120.000424. Epub 2021 Apr 20.
Aging is a progressive, multifactorial, degenerative process in which deleterious changes occur in the biochemistry and function of organs. We showed that angiotensin II (AngII)-induced pathologies in the heart and kidney of young (3-month-old) mice are suppressed by the caveolin-1 scaffolding domain (CSD) peptide. Because AngII mediates many aging-associated changes, we explored whether CSD could reverse pre-existing pathologies and improve organ function in aged mice. Using 18-month-old mice (similar to 60-year-old humans), we found that >5-fold increases in leakage of serum proteins and >2-fold increases in fibrosis are associated with aging in the heart, kidney, and brain. Because tyrosine phosphorylation of cell junction proteins leads to the loss of microvascular barrier function, we analyzed the activation of the receptor tyrosine kinase PDGFR and the nonreceptor tyrosine kinases c-Src and Pyk2. We observed 5-fold activation of PDGFR and 2- to 3-fold activation of c-Src and Pyk2 in aged mice. Treatment with CSD for 4 weeks reversed these pathologic changes (microvascular leakage, fibrosis, kinase activation) in all organs almost down to the levels in healthy, young mice. In studies of heart function, CSD reduced the aging-associated increase in cardiomyocyte cross-sectional area and enhanced ventricular compliance in that echocardiographic studies demonstrated improved ejection fraction and fractional shortening and reduced isovolumic relation time. These results suggest that versions of CSD may be developed as treatments for aging-associated diseases in human patients based on the concept that CSD inhibits tyrosine kinases, leading to the inhibition of microvascular leakage and associated fibrosis, thereby improving organ function. SIGNIFICANCE STATEMENT: The caveolin-1 scaffolding domain (CSD) peptide reverses aging-associated fibrosis, microvascular leakage, and organ dysfunction in the heart, kidneys, and brain via a mechanism that involves the suppression of the activity of multiple tyrosine kinases, suggesting that CSD can be developed as a treatment for a wide range of diseases found primarily in the aged.
衰老是一个渐进的、多因素的、退行性过程，其中器官的生物化学和功能发生有害变化。我们表明，血管紧张素 II（AngII）诱导的年轻（3 个月大）小鼠心脏和肾脏的病理学变化被窖蛋白-1 支架结构域（CSD）肽抑制。由于 AngII 介导许多与衰老相关的变化，我们探索了 CSD 是否可以逆转预先存在的病理学并改善老年小鼠的器官功能。使用 18 个月大的小鼠（类似于 60 岁的人类），我们发现心脏、肾脏和大脑中与衰老相关的血清蛋白渗漏增加了 5 倍以上，纤维化增加了 2 倍以上。由于细胞连接蛋白的酪氨酸磷酸化导致微血管屏障功能丧失，我们分析了受体酪氨酸激酶 PDGFR 和非受体酪氨酸激酶 c-Src 和 Pyk2 的激活。我们观察到在老年小鼠中 PDGFR 的激活增加了 5 倍，c-Src 和 Pyk2 的激活增加了 2 至 3 倍。用 CSD 治疗 4 周几乎将所有器官的这些病理变化（微血管渗漏、纤维化、激酶激活）逆转至健康年轻小鼠的水平。在心脏功能研究中，CSD 降低了与衰老相关的心肌细胞横截面积增加，并增强了心室顺应性，超声心动图研究表明射血分数和缩短分数提高，等容关系时间缩短。这些结果表明，基于 CSD 抑制酪氨酸激酶从而抑制微血管渗漏和相关纤维化从而改善器官功能的概念，CSD 的变体可能被开发为人类患者与衰老相关疾病的治疗方法。
窖蛋白-1 支架结构域（CSD）肽通过抑制多种酪氨酸激酶的活性来逆转心脏、肾脏和大脑中与衰老相关的纤维化、微血管渗漏和器官功能障碍，这表明 CSD 可以被开发为治疗广泛的主要发生在老年人中的疾病的方法。
