ADAM15 is required for optimal collagen cross-linking and scar formation following myocardial infarction

Michael Chute, Preetinder K. Aujla, Yingxi Li, Sayantan Jana, Pavel Zhabyeyev, Jaslyn Rasmuson, Caroline A. Owen, Thomas Abraham, Gavin Y. Oudit, Zamaneh Kassiri

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Collagen cross-linking is an important step in optimal scar formation. Myocardial infarction (MI) results in loss of cardiomyocytes that are replaced with a scar (infarct) tissue. Disintegrin and metalloproteinases (ADAMs) are membrane-bound proteases that can interact with molecules intra- and extra-cellularly to mediate various cellular functions. ADAM15 is expressed in the myocardium, however its function in heart disease has been poorly explored. We utilized mice lacking ADAM15 (Adam15−/−) and wildtype (WT) mice. MI, induced by ligation of the left anterior descending artery, resulted in a transient but significant rise in ADAM15 protein in the WT myocardium at 3-days. Following MI, Adam15−/− mice exhibited markedly higher rate of left ventricular (LV) rupture compared to WT mice (66% vs. 15%, p<0.05). Echocardiography and strain analyses showed worsened LV dysfunction in Adam15−/− mice at 3days, prior to the onset of LV rupture. Second harmonic generation imaging revealed significant disarray and reduction in fibrillar collagen density in Adam15−/− compared to WT hearts. This was associated with lower insoluble and higher soluble collagen fractions, reduced cross-linking enzyme, lysyl oxidase-1 (LOX-1), and fibronectin which is required for LOX-1 function, in Adam15−/−-MI hearts. Post-MI myocardial inflammation was comparable between the genotypes. In vitro, primary adult cardiac fibroblasts from Adam15−/− mice showed suppressed activation in response to ischemia (hypoxia+nutrient depletion) compared to WT fibroblasts. Adam15-deficiency was associated with reduced PAK1(p21-activated kinase-1) levels, a regulator of fibronectin and LOX-1 expression. In female mice, the rate of post-MI LV rupture, PAK1 signaling, LOX-1 and fibronectin protein levels were comparable between Adam15−/− and WT, indicating less impact of ADAM15 loss in females post- MI. This study reports a novel function for ADAM15 in collagen cross-linking and optimal scar formation post-MI which may also apply to scar formation in other tissues.

Original languageEnglish (US)
Pages (from-to)127-143
Number of pages17
JournalMatrix Biology
Volume105
DOIs
StatePublished - Jan 2022

All Science Journal Classification (ASJC) codes

  • Molecular Biology

Fingerprint

Dive into the research topics of 'ADAM15 is required for optimal collagen cross-linking and scar formation following myocardial infarction'. Together they form a unique fingerprint.

Cite this