Abstract

Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF. Lumican (LUM) is a collagen binding proteoglycan with increased expression in hearts of patients and mice with HF, however, its role in cardiac function remains poorly understood. To examine the role of LUM in pressure overload induced cardiac remodeling, we subjected LUM knock-out (LUMKO) mice to aortic banding (AB) and treated cultured cardiac fibroblasts (CFB) with LUM. LUMKO mice exhibited increased mortality 1–14 days post-AB. Echocardiography revealed increased LV dilatation, altered hypertrophic remodeling and exacerbated contractile dysfunction in surviving LUMKO 1–10w post-AB. LUMKO hearts showed reduced collagen expression and cross-linking post-AB. Transcriptional profiling of LUMKO hearts by RNA sequencing revealed 714 differentially expressed transcripts, with enrichment of cardiotoxicity, ECM and inflammatory pathways. CFB treated with LUM showed increased mRNAs for markers of myofibroblast differentiation, proliferation and expression of ECM molecules important for fibrosis, including collagens and collagen cross-linking enzyme lysyl oxidase. In conclusion, we report the novel finding that lack of LUM attenuates collagen cross-linking in the pressure-overloaded heart, leading to increased mortality, dilatation and contractile dysfunction in mice.

Highlights

  • Left ventricular (LV) pressure overload, as seen in patients with aortic stenosis and hypertension, leads to concentric LV remodeling

  • We found no differences in heart or lung weight or the expression of cardiac signature molecules of heart failure, ANP and BNP, pathological remodeling and hypertrophy (ACTA1 encoding α-skeletal actin) (Table S2)

  • The present study shows that LUM plays a critical role in cardiac remodeling following LV pressure overload

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Summary

Introduction

Left ventricular (LV) pressure overload, as seen in patients with aortic stenosis and hypertension, leads to concentric LV remodeling. LV chamber stiffness and remodeling is influenced by cardiac collagen accumulation and cross-linking in experimental models of pressure overload[4,5], as well as in patients with HF5. Cardiac fibrosis is a major operating pathophysiological mechanism affecting tissue architecture, electrical conduction, and diastolic and systolic properties of the myocardium[6]. I.e. syndecans and glypicans, are important to pressure overload driven cardiac remodeling processes, including hypertrophic growth, fibrosis and inflammation[8,9,10,11]. Lumican (LUM) is a keratan sulfate small leucine-rich proteoglycan (SLRP) localized to the ECM, and known to regulate collagen fibrillogenesis in connective tissues, e.g. cornea, tendon and skin[12,13]. We investigated the hypothesis that LUM is important for cardiac remodeling, fibrosis and inflammation following experimental pressure overload of the heart. LUM knock-out (LUMKO) mice were subjected to aortic banding (AB) in vivo, and cultured cardiac fibroblasts were treated with LUM in vitro

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