Susic Dinko, Varagic Jasmina, Ahn Jwari, Frohlich Edward D
Hypertension Research Laboratory, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, USA.
Curr Opin Cardiol. 2004 Jul;19(4):336-40. doi: 10.1097/01.hco.0000127135.73849.4f.
Advanced glycation end-products accumulate on body proteins with aging, and their formation is greatly enhanced with rising plasma glucose level. Advanced glycation end-products bond together and, consequently, increase protein crosslinking. In the circulatory system, increased collagen crosslinking caused by advanced glycation end-products increases cardiovascular stiffness as well as the risk for cardiovascular morbidity and mortality. A breaker of advanced glycation end-products-related crosslinks, ALT-711, has been recently discovered. This review summarizes the latest evidence that breaking collagen crosslinks may be an efficient new therapeutic approach to the adverse cardiovascular and renal consequences of aging and diabetes.
The results of recent studies clearly demonstrated that ALT-711, a breaker of advanced glycation end-products-related protein crosslinks, ameliorated the adverse cardiovascular and renal changes associated with aging, diabetes, and hypertension. In diabetic animals, ALT-711 improved left ventricular function, decreased ventricular collagen content and improved its solubility, reduced aortic stiffness, ameliorated diabetic nephrosclerosis, and improved renal function. In older spontaneously hypertensive rats, it reduced left ventricular mass and collagen content, reduced proteinuria, and extended survival. The results of recent studies also indicated that the effects of crosslinks breakers may be mediated in part via reduction in oxidative stress and profibrotic cytokines.
The results of experimental studies and one clinical trial have clearly established the usefulness of ALT-711 in the therapy of the cardiovascular and renal disorders associated with aging, diabetes, and hypertension. Thus, breaking advanced glycation end-products-related collagen crosslinks has emerged as a new approach to cardiovascular therapy.
随着年龄增长，晚期糖基化终产物在人体蛋白质上积累，且随着血浆葡萄糖水平升高其形成会显著增强。晚期糖基化终产物相互结合，从而增加蛋白质交联。在循环系统中，晚期糖基化终产物导致的胶原蛋白交联增加会使心血管硬度增加，以及心血管发病和死亡风险升高。最近发现了一种晚期糖基化终产物相关交联的破坏剂ALT - 711。本综述总结了最新证据，即破坏胶原蛋白交联可能是一种有效的新治疗方法，可应对衰老和糖尿病带来的不良心血管及肾脏后果。
近期研究结果清楚地表明，ALT - 711作为一种晚期糖基化终产物相关蛋白质交联的破坏剂，改善了与衰老、糖尿病和高血压相关的不良心血管及肾脏变化。在糖尿病动物中，ALT - 711改善了左心室功能，降低了心室胶原蛋白含量并提高了其溶解性，降低了主动脉硬度，改善了糖尿病性肾硬化，并改善了肾功能。在老年自发性高血压大鼠中，它降低了左心室质量和胶原蛋白含量，减少了蛋白尿，并延长了生存期。近期研究结果还表明，交联破坏剂的作用可能部分通过降低氧化应激和促纤维化细胞因子来介导。
实验研究和一项临床试验的结果已明确证实ALT - 711在治疗与衰老、糖尿病和高血压相关的心血管及肾脏疾病方面的有效性。因此，破坏晚期糖基化终产物相关的胶原蛋白交联已成为心血管治疗的一种新方法。
