Abstract

Background: Tenascin-C (TN-C) plays a maladaptive role in left ventricular (LV) hypertrophy following pressure overload. However, the role of TN-C in LV regression following mechanical unloading is unknown. Methods: LV hypertrophy was induced by transverse aortic constriction for 10 weeks followed by debanding for 2 weeks in wild type (Wt) and TN-C knockout (TN-C KO) mice. Cardiac function was assessed by serial magnetic resonance imaging. The expression of fibrotic markers and drivers (angiotensin-converting enzyme-1, ACE-1) was determined in LV tissue as well as human cardiac fibroblasts (HCFs) after TN-C treatment. Results: Chronic pressure overload resulted in a significant decline in cardiac function associated with LV dilation as well as upregulation of TN-C, collagen 1 (Col 1), and ACE-1 in Wt as compared to TN-C KO mice. Reverse remodeling in Wt mice partially improved cardiac function and fibrotic marker expression; however, TN-C protein expression remained unchanged. In HCF, TN-C strongly induced the upregulation of ACE 1 and Col 1. Conclusions: Pressure overload, when lasting long enough to induce HF, has less potential for reverse remodeling in mice. This may be due to significant upregulation of TN-C expression, which stimulates ACE 1, Col 1, and alpha-smooth muscle actin (α-SMA) upregulation in fibroblasts. Consequently, addressing TN-C in LV hypertrophy might open a new window for future therapeutics.

Highlights

  • IntroductionLeft ventricular hypertrophy (LVH) is an adaptive mechanism of the heart to compensate for pressure overload

  • Left ventricular hypertrophy was induced by transverse aortic constriction (TAC)

  • Debanding resulted in a significant reduction in both heart weight and heart weight-to-body weight ratio in wild type (Wt) 12 (p < 0.05) whereas this regression was less pronounced in TN-C knockout (TN-C KO) 12

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Summary

Introduction

Left ventricular hypertrophy (LVH) is an adaptive mechanism of the heart to compensate for pressure overload. This was described in a landmark clinical paper by William. One study suggested that mechanical reduction of left ventricular (LV) afterload significantly reduced LV wall stress [3], in a mechanism described by Levin et al [4] as “reverse remodeling”. Tenascin-C (TN-C) plays a maladaptive role in left ventricular (LV) hypertrophy following pressure overload. Results: Chronic pressure overload resulted in a significant decline in cardiac function associated with LV dilation as well as upregulation of TN-C, collagen 1 (Col 1), and ACE-1 in Wt as compared to TN-C KO mice. In HCF, TN-C strongly induced the upregulation of ACE 1 and Col

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