Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction.
2011, J Mol Cell Cardiol. 2011 Mar;50(3):522-33. Epub 2011 Jan 8.
Vilahur G, Juan-Babot O, Peña E, Oñate B, Casaní L, Badimon L.
Autors del centre relacionats: Badimon Lina, Casaní Laura, Juan Oriol, Peña Esther, Vilahur Gemma, Oñate Blanca.
Vilahur G, Juan-Babot O, Peña E, Oñate B, Casaní L, Badimon L.
Autors del centre relacionats: Badimon Lina, Casaní Laura, Juan Oriol, Peña Esther, Vilahur Gemma, Oñate Blanca.
Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CIBEROBN-Pathophysiology of Obesity and Nutrition, Barcelona, Spain.
Abstract
The extent of cardiac remodeling determines survival after acute MI. However, the mechanisms driving cardiac remodeling remain unknown. We examined the effect of ischemia and reperfusion (R) on myocardial changes up to 6days post-MI. Pigs underwent 1.5h or 4h mid-LAD balloon occlusion and sacrificed or 1.5h occlusion followed by R and sacrificed at 2.5h, 1day, 3days, and 6days. Ischemic- (IM) and non-ischemic myocardium (NIM) was obtained for molecular analysis of: 1) apoptosis (P-Bcl2, Bax, P-p53, active-caspase-3); 2) the TLR-4-MyD88-dependent and independent pathways; 3) Akt/mTOR/P70(S6K) axis activation; and, 4) fibrosis (TGF-β, collagen1-A1/A3). Histopathology for inflammation, collagen, and fibroblast content, TUNEL staining, and metalloproteinase activity was performed. Apoptosis is only detected upon R in IM cardiomyocytes and progresses up to 6days post-R mainly associated with infiltrated macrophages. The Akt/mTOR/P70(s6K) pathway is also activated upon R (IM) and remains elevated up to 6days-R (P<0.05). Ischemia activates the TLR-4-MyD88-dependent (cytokines/chemokines) and -independent (IRF-3) pathways in IM and NIM and remains high up to 6days post-R (P<0.05). Accordingly, leukocytes and macrophages are progressively recruited to the IM (P<0.05). Ischemia up-regulates pro-fibrotic TGF-β that gradually rises collagen1-A1/-A3 mRNA with subsequent increase in total collagen fibrils and fibroblasts from 3days-R onwards (P<0.005). MMP-2 activity increases from ischemia to 3days post-R (P<0.05). We report that there is a timely coordinated cellular and molecular response to myocardial ischemia and R within the first 6days after MI. In-depth understanding of the mechanisms involved in tissue repair is warranted to timely intervene and better define novel cardioprotective strategies.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Abstract
The extent of cardiac remodeling determines survival after acute MI. However, the mechanisms driving cardiac remodeling remain unknown. We examined the effect of ischemia and reperfusion (R) on myocardial changes up to 6days post-MI. Pigs underwent 1.5h or 4h mid-LAD balloon occlusion and sacrificed or 1.5h occlusion followed by R and sacrificed at 2.5h, 1day, 3days, and 6days. Ischemic- (IM) and non-ischemic myocardium (NIM) was obtained for molecular analysis of: 1) apoptosis (P-Bcl2, Bax, P-p53, active-caspase-3); 2) the TLR-4-MyD88-dependent and independent pathways; 3) Akt/mTOR/P70(S6K) axis activation; and, 4) fibrosis (TGF-β, collagen1-A1/A3). Histopathology for inflammation, collagen, and fibroblast content, TUNEL staining, and metalloproteinase activity was performed. Apoptosis is only detected upon R in IM cardiomyocytes and progresses up to 6days post-R mainly associated with infiltrated macrophages. The Akt/mTOR/P70(s6K) pathway is also activated upon R (IM) and remains elevated up to 6days-R (P<0.05). Ischemia activates the TLR-4-MyD88-dependent (cytokines/chemokines) and -independent (IRF-3) pathways in IM and NIM and remains high up to 6days post-R (P<0.05). Accordingly, leukocytes and macrophages are progressively recruited to the IM (P<0.05). Ischemia up-regulates pro-fibrotic TGF-β that gradually rises collagen1-A1/-A3 mRNA with subsequent increase in total collagen fibrils and fibroblasts from 3days-R onwards (P<0.005). MMP-2 activity increases from ischemia to 3days post-R (P<0.05). We report that there is a timely coordinated cellular and molecular response to myocardial ischemia and R within the first 6days after MI. In-depth understanding of the mechanisms involved in tissue repair is warranted to timely intervene and better define novel cardioprotective strategies.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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