Myocardial overexpression of TIMP3 following myocardial infarction exerts beneficial effects through promoting angiogenesis and suppressing early proteolysis.

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Myocardial overexpression of TIMP3 following myocardial infarction exerts beneficial effects through promoting angiogenesis and suppressing early proteolysis.

Am J Physiol Heart Circ Physiol. 2017 May 26;:ajpheart.00108.2017

Authors: Takawale A, Zhang P, Azad A, Wang W, Wang X, Murray AG, Kassiri Z

Abstract
Myocardial infarction (MI) results in loss of cardiomyocytes, adverse extracellular matrix (ECM) and structural remodeling, left ventricular (LV) dilation and dysfunction. Tissue inhibitor of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the main regulators of ECM turnover. TIMPs also have MMP-independent functions. TIMP3 levels are reduced in the heart within 24 hours of MI in mice. We investigated if overexpression of TIMP3 post-MI limits adverse remodeling, LV dilation and dysfunction. MI was induced by LAD ligation in 10-12 weeks old male C57BL/6J mice, and adenoviral constructs expressing human TIMP3 (Ad-hTIMP3) or no TIMP (Ad-Null) were injected in the peri-infarct zone (5.4x10(7) pfu/heart, 5 injections/heart). Cardiac function assessed by echocardiography showed improved LV physiology and reduced LV dilation following TIMP3 overexpression compared to Ad-Null-MI group. Post-MI adverse remodeling was attenuated in Ad-TIMP3-MI group as assessed by greater cardiomyocyte density, less infarct expansion and ECM disruption). TIMP3 overexpression blunted the early rise in proteolytic activities post-MI. A higher density of coronary arteries, and a greater number of proliferating endothelial cells were detected in the infarct and peri-infarct regions in Ad-TIMP3-MI compared to Ad-null-MI group. In vitro 3D angiogenesis assay confirmed that rTIMP3 promotes angiogenesis in human endothelial cells, although biphasically and in a dose-dependent manner. Intriguingly, overexpression of Ad-hTIMP3 at 10-fold higher concentration had no beneficial effects, consistent with anti-angiogenic effects of TIMP3 at higher doses. In conclusion, optimal overexpression of TIMP3 can be a promising therapeutic approach to limit adverse post-MI remodeling by dually inhibiting early proteolysis and promoting angiogenesis.

PMID: 28550172 [PubMed - as supplied by publisher]

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