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
Summary
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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