The Role of Interleukin-1! on the Expression of Nestin in Cardiac Neural Stem cells Following Myocardial Infarction

Mémoire présentée à la Faculté de médecine en vue de l'obtention du grade de maîtrise en physiologie ABSTRACT ii The underlying biological event(s) implicated in the increased expression of nestin in cardiac resident neural stem cells (NSC) following myocardial infarction (MI) remain unknown. Past studies have shown that dexamethasone treatment, a synthetic glucocorticoid with potent anti-inflammatory properties, abolished the upregulation of nestin in the non-infacted left ventricle (NILV) following MI. This suggests an association with the inflammatory response. The present study tested the hypothesis that the inflammatory cytokine interleukin-1! (IL-1!) can influence the neural stem cell phenotype. A secondary goal of the study was to assess impact of IL-1! signalling inhibition on cardiac function and wound healing following MI. Following complete coronary artery ligation of the adult male rat heart, left ventricular contractile dysfunction was associated with the upregulation of the pro-apoptotic protein bax, the anti-apoptotic protein Bcl-2 and nestin in the non-infarcted myocardium. Xoma 052 (1 mg/kg), an IgG antibody directed against IL-1!, was administred 24 hrs after ischemic injury and subsequently injected 2x over a period of 21 days. Treatment did not alter infarct size or improve left ventricular contractility. In addition, it failed to abolish the increased expression of nestin and Bcl-2, and modestly reduced bax protein levels. To directly assess the relationship between inflammation and the expression of nestin in the absence of an ischemic insult, adult male rats were injected with lipopolysaccharide (LPS) (10mg/kg;18 hrs). In the heart of LPS-treated rats, IL-1! mRNA levels were significantly increased and associated with elevated nestin protein expression. The pre-treatment with Xoma 052 (10mg/kg) abolished the increased expression of nestin in the heart of LPS-treated rats. These data indicate that neural stem cells may represent a target for IL-1!. However, futher investigation is required to elucidate the role of IL-1! on NSC following MI. iii cellules souches neurales pourraient représenter une cible potentielle de l'IL-1!.