CXCL12γ isoform inhibits adverse left ventricular remodeling after acute myocardial infarction

Abstract

The chemokine CXCL12 is essential for cardiovascular system development and plays a major role in physio-pathological processes such as inflammation, angiogenesis but also tissue remodeling after an ischemic insult. In addition to the binding to its receptors, CXCR4 and CXCR7, CXCL12 interaction with heparan-sulfates (HS) commands its biological activity. Studies in experimental models of myocardial infarction (MI) revealed a protective role for CXCL12α. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a pivotal role in tissue repair. The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI. MI are induced in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI), harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression is also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis and evaluation of infarct size, interstitial fibrosis, capillary and arteriole densities and as well as inflammatory cell infiltration. After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice normalizes cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. We show that CXCL12γ isoform plays an important role in the regulation of cardiac function after MI and that its interactions with HS seems essential for adequate cardiac repair.