PDF(Pubmed)
Abstract：
Heart failure remains one of the largest clinical burdens globally, with little to no improvement in the development of disease-eradicating therapeutics. Integrin targeting has been used in the treatment of ocular disease and cancer, but little is known about its utility in the treatment of heart failure. Here we sought to determine whether the second generation orally available, αvβ3-specific RGD-mimetic, 29P , was cardioprotective. Male mice were subjected to transverse aortic constriction (TAC) and treated with 50 μg/kg 29P or volume-matched saline as Vehicle control. At 3 weeks post-TAC, echocardiography showed that 29P treatment significantly restored cardiac function and structure indicating the protective effect of 29P treatment in this model of heart failure. Importantly, 29P treatment improved cardiac function giving improved fractional shortening, ejection fraction, heart weight and lung weight to tibia length fractions, together with partial restoration of Ace and Mme levels, as markers of the TAC insult. At a tissue level, 29P reduced cardiomyocyte hypertrophy and interstitial fibrosis, both of which are major clinical features of heart failure. RNA sequencing identified that, mechanistically, this occurred with concomitant alterations to genes involved molecular pathways associated with these processes such as metabolism, hypertrophy and basement membrane formation. Overall, targeting αvβ3 with 29P provides a novel strategy to attenuate pressure-overload induced cardiac hypertrophy and fibrosis, providing a possible new approach to heart failure treatment.
摘要：
心力衰竭仍然是全球最大的临床负担之一。在根除疾病疗法的发展方面几乎没有改善。整合素靶向已用于眼部疾病和癌症的治疗，但人们对其在心力衰竭治疗中的作用知之甚少。在这里，我们试图确定第二代口服是否可用，αvβ3特异性RGD模拟物，29P,对心脏有保护作用.使雄性小鼠经受横向主动脉缩窄(TAC)并用50μg/kg29P或体积匹配的盐水作为媒介物对照处理。在TAC后3周，超声心动图显示29P治疗能显著恢复心功能和结构,提示29P治疗对心力衰竭模型有保护作用。重要的是,29P治疗改善心脏功能，改善缩短分数，射血分数,心脏重量和肺重量对胫骨长度分数，连同Ace和Mme水平的部分恢复，作为TAC侮辱的标志。在组织层面,29P减少心肌细胞肥大和间质纤维化，两者都是心力衰竭的主要临床特征。RNA测序发现，机械上,这伴随着与这些过程相关的分子途径如代谢相关的基因的改变而发生，肥大和基底膜形成。总的来说,用29P靶向αvβ3提供了一种新的策略来减轻压力超负荷诱导的心脏肥大和纤维化，为心力衰竭治疗提供可能的新方法。
