Les effets cardioprotecteurs de peptides dérivés des sécrétagogues de l’hormone de croissance dans le modèle d’ischémie-reperfusion du myocarde murin

Growth hormone-releasing peptides (GHRP) are synthetic peptides that stimulate growth hormone (GH) secretion after binding with the ghrelin receptor (previously known as the growth hormone secretagogue receptor 1a, GHS-R1a). Unacylated ghrelin (UAG) represents the predominant form of ghrelin in circulation, but UAG does not bind to the ghrelin receptor and does not stimulate GH release. Studies have shown that GHRPs and UAG possess cardioprotective effects independent from GH secretion. The group of Ong has identified the CD36 receptor, expressed in cardiomyocytes, macrophages and adipocytes among other cells, as the second binding site for GHRPs, whereas the receptor for UAG is still unknown until this day. The general aim of this thesis was to evaluate the cardioprotective effects of a new class of GHRPs analogues, the azapeptides, which show a higher selectivity towards the CD36 receptor in comparison to that of ghrelin, and the cardioprotective effects of a bioactive peptide fragment of UAG, UAG6-13, in the pathology of ischemic heart disease.   The model of myocardial ischemia/reperfusion (MI/R) was generated by a surgical ligation of the left anterior descending coronary artery for 30 min to induce an ischemia, followed by a reperfusion of 6 or 48 h in C57BL/6 male mice. The mice have been pretreated in the first study with azapeptide CP-3(iv) (289 nmol/kg) or the vehicle (0.9% NaCl) daily by subcutaneous (s.c.) injection, and in the second study with UAG (100 nmol/kg), UAG6-13 (1000 nmol/kg and 3000 nmol/kg) or the vehicle twice daily by s.c. injection prior to being subjected to MI/R.   Our first study have shown that CP-3(iv) protects against I/RM induced injury by reducing the infarct size and preserving myocardial hemodynamics. These effects result, in part, by an increase in adiponectin production/secretion and proteins involved in its transcription in adipose tissue. This leads to an increase in circulating levels of adiponectin and a decrease in plasma concentration of non-esterified fatty acids. In the myocardium, the anti-oxidative, anti-apoptotic and pro-metabolic properties of adiponectin has been observed. None of these effects was observed in CD36 deficient mice and the function recovery of the heart by CP-3(iv) has been abrogated by an anti-adiponectin antibody in an isolated heart model, showing the dependency for the CD36 receptor and the importance of the role of adiponectin to mediate the cardioprotective effects of CP-3(iv). Our second study showed that UAG and UAG6-13 have reduced the percentage of myocardial lesions and preserved cardiac hemodynamics. These effects result largely by a reduction in plasma concentration of pro-inflammatory cytokines IL-6 and TNF-α. Moreover, our results have shown a reduction in apoptosis and an activation of the AMPK pathway involved in fatty acids oxidation in the heart. The effects of UAG6-13 are independent of the ghrelin receptor as shown by a concomitant addition of D-Lys3-GHRP-6, a ghrelin receptor antagonist, in the model of isolated heart.   In conclusion, the work conducted in this thesis have shown that CP-3(iv) and UAG6-13 possess potent cardioprotective effects in the pathology of MI/R and constitute new therapeutic approaches which can be applied in ischemic cardiovascular disease.

Keyphrases: CD36, Growth hormone secretagogues, CD36, Unacylated ghrelin, Myocardial ischemia/reperfusion, Adiponectin, Ghrelin receptor