Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics is a major contributor to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti-cancer Arg-Gly-Asp (RGD)-mimetic pentapeptide, cilengitide, here used at low doses. Cilengitide targets αvβ3 integrin and this protein is upregulated in human dilated and ischaemic cardiomyopathies. Treatment of mice after abdominal aortic constriction (AAC) surgery with low-dose cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with an associated reduction in disease severity. At a molecular level, ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles, with a significant enhancement of pro-angiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment. Moreover, ldCil treatment of Angiotensin II-stimulated AngII-stimulated cardiomyocytes significantly restores transcriptomic profiles similar to those found in normal human heart. The significance of this finding is enhanced by transcriptional similarities between AngII-treated cardiomyocytes and failing human hearts. Taken together, our data provide evidence supporting a possible new strategy for improved heart failure treatment using low-dose RGD-mimetics with relevance to human disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

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重新利用抗癌药物来治疗肥厚性心脏病。


冠状动脉微血管功能障碍与适应不良的心肌细胞形态和能量学相结合是心力衰竭进展的主要原因。因此，双重增强心脏血管生成和靶向心肌细胞功能以减缓或逆转心力衰竭的发展是改善治疗的合理步骤。我们提供的证据表明，西仑吉肽有可能重新利用以前的抗癌精氨酸-甘氨酸-天冬氨酸（RGD）模拟五肽，西仑吉肽在这里以低剂量使用。西仑吉肽靶向 αvβ3 整合素，该蛋白在人类扩张型心肌病和缺血性心肌病中表达上调。用低剂量西仑吉肽 (ldCil) 治疗腹主动脉缩窄 (AAC) 手术后的小鼠可增强冠状血管生成，并直接影响心肌细胞肥大，从而降低疾病严重程度。在分子水平上，ldCil 治疗对心脏内皮细胞转录组谱有直接影响，显着增强促血管生成信号通路，证实了 ldCil 治疗后增强的血管生成表型。此外，对血管紧张素 II 刺激的心肌细胞进行 ldCil 处理可显着恢复与正常人心脏中发现的转录组谱相似的转录组谱。 AngII处理的心肌细胞和衰竭的人类心脏之间的转录相似性增强了这一发现的重要性。总而言之，我们的数据提供了证据支持一种可能的新策略，该策略可使用与人类疾病相关的低剂量 RGD 模拟物来改善心力衰竭治疗。 © 2019 作者。 《病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。