Abstract
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.
Highlights
Heart failure affects approximately 26 million people worldwide and is characterised by insufficient cardiac function, poor coronary microvascular reactivity and maladaptive cardiomyocyte hypertrophy
Results β3-integrin expression is elevated in human dilated and ischaemic cardiomyopathies To test the utility of low dose cilengitide, ldCil, in the treatment heart failure we first examined the expression of its target, β3-integrin, in human non-failing heart, non-failing hypertrophic heart, and dilated- and ischaemic-cardiomyopathies
Since heart failure is associated with reduced blood flow to the heart, and we have published previously that ldCil can increase blood vessel density in pathological angiogenesis [27], we examined cardiac capillary density after abdominal aortic constriction (AAC) surgery
Summary
Heart failure affects approximately 26 million people worldwide and is characterised by insufficient cardiac function, poor coronary microvascular reactivity and maladaptive cardiomyocyte hypertrophy. LdCil does not act as an αvβ3-integrin antagonist and does not affect cell adhesion or migration, but instead alters αvβ3-signalling to enhance the activation and recycling of the major pro-angiogenic receptor VEGF-receptor 2 [27] We have exploited these features of ldCil to improve chemotherapy efficacy in cancer models in vivo by increasing tumour blood vessel number and directly enhancing chemotherapy delivery and metabolism in malignant cells [28]. Taken together, these data support ldCil treatment as a strategy to affect αvβ3-integrin signalling without affecting cell adhesion and migration. These data indicate that repurposing cilengitide may have salutary impact on human heart failure
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