Effects of pericyte and smooth muscle specific knock-out of CXCL12 on cardiac function after myocardial ischemia in mice

Abstract

Abstract Introduction Ischemic cardiomyopathy as a result of myocardial infarction represents one of the most common causes of heart failure (1). The C-X-C motif chemokine ligand 12 (CXCL12) and its receptor CXCR4 facilitate cardiac repair after myocardial ischemia (MI) and play fundamental roles in cardiovascular development (2). However, the cell- and tissue-specific actions of CXCL12 are poorly understood, limiting the introduction of targeted therapies. Here, we aimed to examine the role of pericyte and smooth muscle cell-specific CXCL12 expression on myocardial function after MI. Methods We generated a smooth muscle protein 22-alpha-Cre and a pericyte protein NG2-Cre driven mouse model to ablate CXCL12 specifically in smooth muscle cells (SM22-Cre x CXCL12flox/flox) and in pericytes (NG2-Cre x CXCL12flox/flox). Genotyping was performed using ear hole biopsy by PCR. Hearts were analysed morphologically by histology and immunofluorescence. Cardiac function and dimensions of the wall thicknesses and cardiac cavities were determined by echocardiography. Myocardial infarction was induced in the animals and cardiac function was further investigated 28 days after MI. Results In immunofluorescence, we found that CXCL12 is highly expressed in SM22+ smooth muscle cells and in cells surrounding arterial blood vessels (3). NG2-CXCL12-/- mice did not show increased mortality, they behaved inconspicuously and no obvious developmental defects could be detected. Echocardiographic analysis of cardiac function in NG2-Cre x CXCL12flox/flox mice without infarction showed no significant difference in left ventricular (LV) performance and no evidence of abnormal geometry of the ventricles compared with controls. Assessment of SM22-Cre x CXCL12flox/flox mice after MI revealed reduced ejection fraction (EF) (29.0%±9.7 vs. 40.0%±8.1; n=10; p=0.027) and stroke volume (SV) (19.0µl±3.3 vs. 32.7µl±10.3; n=10; p=0.002) compared to non-transgenic controls. In contrast NG2-Cre x CXCL12flox/flox mice showed no significant changes in EF (34.6%±11.4 vs. 40.0%±8.1; n=10; p=0.368) and SV (27.7µl±7.3 vs. 32.7µl±10.3; n=10; p=0.303). Conclusion Our findings suggest that pericyte specific CXCL12 plays no major role in cardiac development and function after MI. In contrast, KO of CXCL12 in smooth muscle seems to deteriorate cardiac function after ischemia.