Adcy9 Gene Inactivation Improves Cardiac Function After Myocardial Infarction in Mice.

Autor: Ferron M; Montréal Heart Institute, Montréal, Québec, Canada., Merlet N; Montréal Heart Institute, Montréal, Québec, Canada., Mihalache-Avram T; Montréal Heart Institute, Montréal, Québec, Canada., Mecteau M; Montréal Heart Institute, Montréal, Québec, Canada., Brand G; Montréal Heart Institute, Montréal, Québec, Canada., Gillis MA; Montréal Heart Institute, Montréal, Québec, Canada., Shi Y; Montréal Heart Institute, Montréal, Québec, Canada., Nozza A; Montréal Health Innovations Coordinating Centre (MHICC), Montréal, Québec, Canada., Cossette M; Montréal Health Innovations Coordinating Centre (MHICC), Montréal, Québec, Canada., Guertin MC; Montréal Health Innovations Coordinating Centre (MHICC), Montréal, Québec, Canada., Rhéaume E; Montréal Heart Institute, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montréal, Québec, Canada., Tardif JC; Montréal Heart Institute, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montréal, Québec, Canada. Electronic address: jean-claude.tardif@icm-mhi.org.
Jazyk: angličtina
Zdroj: The Canadian journal of cardiology [Can J Cardiol] 2023 Jul; Vol. 39 (7), pp. 952-962. Date of Electronic Publication: 2023 Apr 11.
DOI: 10.1016/j.cjca.2023.04.005
Abstrakt: Background: Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity.
Methods: Wild-type (WT) and Adcy9-inactivated (Adcy9 Gt/Gt ) male mice, transgenic or not for human CETP (tgCETP +/- ), were subjected to MI by permanent left anterior descending coronary artery ligation and studied for 4 weeks. Left ventricular (LV) function was assessed by echocardiography at baseline, 1, and 4 weeks after MI. At sacrifice, blood, spleen and bone marrow cells were collected for flow cytometry analysis, and hearts were harvested for histologic analyses.
Results: All mice developed LV hypertrophy, dilation, and systolic dysfunction, but Adcy9 Gt/Gt mice exhibited reduced pathologic LV remodelling and better LV function compared with WT mice. There were no differences between tgCETP +/- and Adcy9 Gt/Gt tgCETP +/- mice, which both exhibited intermediate responses. Histologic analyses showed smaller cardiomyocyte size, reduced infarct size, and preserved myocardial capillary density in the infarct border zone in Adcy9 Gt/Gt vs WT mice. Count of bone marrow T cells and B cells were significantly increased in Adcy9 Gt/Gt mice compared with the other genotypes.
Conclusions: Adcy9 inactivation reduced infarct size, pathologic remodelling, and cardiac dysfunction. These changes were accompanied by preserved myocardial capillary density and increased adaptive immune response. Most of the benefits of Adcy9 inactivation were only observed in the absence of CETP.
(Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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