Loss of miR-144 signaling interrupts extracellular matrix remodeling after myocardial infarction leading to worsened cardiac function

Quan He,Jeanne James,Jing Li,Takashi Honda,Fangfei Wang,Andrew Redington

doi:10.1038/s41598-018-35314-6

Quan He, Jeanne James + Show 4 more

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https://doi.org/10.1038/s41598-018-35314-6

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Abstract

We have previously shown that MicroRNA (miR) -144 is a key modulator of the acute cardioprotection associated with remote ischemic preconditioning and post myocardial infarction (MI) remodeling. In this study we examine the biology of the remodeling response after permanent ligation of the left anterior descending coronary artery in male miR-144 KO mice, and wild-type littermates (WT). Collagen content and cross linking were determined by hydroxyproline and pyridinoline assays, MI size and scar thickness were measured post PicoSirius Red staining, and cardiac function was evaluated by echocardiography. miR-144 KO mice developed normally with normal cardiac function, however after MI, infarction size was greater and scar thickness was reduced in miR-144 KO mice compared with WT littermates. miR-144 KO mice had a lower incidence of acute cardiac rupture compared with WT littermates early after MI but there was impaired late remodeling, reflected by increased total cardiac collagen content and collagen cross-linkage associated with changes in Zeb1/LOX1 axis, and decreased left ventricular ejection fraction. We conclude that miR-144 is involved in extracellular matrix remodeling post MI and its loss leads to increased myocardial fibrosis and impaired functional recovery.

Highlights

Cardiac extracellular matrix (ECM) is a three dimensional dynamic structure composed of a basement membrane, interstitial matrix and extracellular fluid
Collagen biosynthesis and maturation is a complex process composed of several steps including translation and post translational modification of three procollagen chains folding into a triple helix, multiple triple helix self-assembly, and inter triple helix cross-linking catalyzed by lysyle oxidases (LOX)[2]
As ECM remodeling greatly affects scar formation after myocardial infarction, we evaluated the scar formation in miR-144 KO mice subjected to left anterior descending coronary artery occlusion

Summary

Introduction

Cardiac extracellular matrix (ECM) is a three dimensional dynamic structure composed of a basement membrane, interstitial matrix and extracellular fluid. Collagen biosynthesis and maturation is a complex process composed of several steps including translation and post translational modification (hydroxylation and glycosylation) of three procollagen chains folding into a triple helix, multiple triple helix self-assembly, and inter triple helix cross-linking catalyzed by lysyle oxidases (LOX)[2]. Pyridinoline and hydroxyproline contents are key targets for collagen cross linking and concentration. As the major structural protein in cardiac ECM, collagens have significant impact on cardiac remodeling post MI, in respect of their concentration and their cross linking[5]. With myocardial fibrosis[6], and enhanced collagen cross linking results in stronger post-infarct scar and reduced left ventricular myocardial distensibility, in turn leading to cardiac dysfunction[7]. We have recently shown that miR-144 loss-of-function increases, and miR-144 supplementation reduces, post myocardial infarction remodeling[13,14]. We first characterized global functional responses in the miR-144 KO strain and examined the acute and chronic structural and functional responses to myocardial infarction

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