α7‐nAChR‐Mediated Therapeutic Angiogenesis Accounts for the Advantageous Effect of Low Nicotine Doses Against Myocardial Infarction in Rats

Abstract

Angiogenesis accelerates tissue regeneration in a variety of ischemic conditions including myocardial infarction (MI) and constitutes a valuable approach for post‐MI repair. Here we investigated whether angiogenesis promotion induced by α7‐nicotinic acetylcholine receptors (α7‐nAChRs) mitigates histopathological, electrocardiographic, and molecular consequences of MI in rats. These profiles were evaluated in rats with isoprenaline (85 mg/kg/day i.p. for 2 days)‐induced MI and co‐treated subcutaneously with nicotine (20 μg/kg/day s.c.), PHA‐543613 (PHA, selective α7‐nAChR agonist, 20 μg/kg/day), methyllycaconitine (MLA, selective α7‐nAChR antagonist, 40 μg/kg/day) plus nicotine, or the vehicle for 16 consecutive days. Isoprenaline‐insulted rats showed (i) ECG signs of MI such as significant ST‐segment elevations and prolonged QT‐intervals, (ii) deteriorated left ventricular histopathological scoring and elevated inflammatory cell infiltration, (iii) reduced immunohistochemical expression of cardiac CD34, a biomarker of capillary density, (iv) decreased cardiac expression of iNOS and α7‐nAChRs, and (v) adaptive increases in cardiac HO‐1 expression and plasma angiogenic markers such as vascular endothelial growth factor (VEGF) and nitric oxide (NO). These effects of isoprenaline, except cardiac iNOS and α7‐nAChRs downregulation, were ameliorated in rats co‐treated with nicotine or the selective α7‐nAChR agonist PHA for 16 consecutive days. We also show that concurrent α7‐nAChR blockade by MLA reversed the ECG, histopathological, and capillary density effects of nicotine, thereby reinforcing the advantageous cardioprotective and anti‐ischemic roles of α7‐nAChRs in this setting. In conclusion, the activation of α7‐nAChRs with PHA or doses of nicotine in the microgram scale promotes neovascularization and offers a promising therapeutic strategy for MI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.