Abstract
Krüppel-like factors (KLFs) are a family of transcription factors which play important roles in the heart under pathological and developmental conditions. We previously identified and cloned Klf6 whose homozygous mutation in mice results in embryonic lethality suggesting a role in cardiovascular development. Effects of KLF6 on pathological regulation of the heart were investigated in the present study. Mice heterozygous for Klf6 resulted in significantly diminished levels of cardiac fibrosis in response to angiotensin II infusion. Intriguingly, a similar phenotype was seen in cardiomyocyte-specific Klf6 knockout mice, but not in cardiac fibroblast-specific knockout mice. Microarray analysis revealed increased levels of the extracellular matrix factor, thrombospondin 4 (TSP4), in the Klf6-ablated heart. Mechanistically, KLF6 directly suppressed Tsp4 expression levels, and cardiac TSP4 regulated the activation of cardiac fibroblasts to regulate cardiac fibrosis. Our present studies on the cardiac function of KLF6 show a new mechanism whereby cardiomyocytes regulate cardiac fibrosis through transcriptional control of the extracellular matrix factor, TSP4, which, in turn, modulates activation of cardiac fibroblasts.
Highlights
Fibrosis is a hallmark pathological feature of end-stage organ damage.[1]
Pressure overload by transverse aortic banding (TAC) to wild-type and Klf6+/- mice did not show difference in cardiac fibrosis (Fig. 1G and H), relative heart weight (Fig. 1I), hemodynamic analysis (Supplemental Fig. 1F-H and Supplemental table1) or echocardiographic function (Supplemental Fig.2D). Both angiotensin Angiotensin II (II) and Transverse Aortic Constriction (TAC) treatment were performed for 14 days and induced significant cardiac fibrosis in wild-type mice
Klf6flox/-;αMHC-Cre mice did not show difference in systolic blood pressure under angiotensin II treatment or pressure-overload compared to Klf6+/- mice (Supplemental Fig.1I, J). These results showed that cardiomyocyte expression of KLF6 is indispensable for cardiac fibrotic progression by angiotensin II, and a possible signaling pathway from cardiomyocytes to cardiac fibroblasts in this process
Summary
Fibrosis is a hallmark pathological feature of end-stage organ damage.[1]. Persistent pathological stimulation promotes a plethora of responses including inflammatory cell infiltration, destruction of parenchymal cell structure, excess extracellular matrix (ECM) deposition by myofibroblasts, and lack of tissue reconstruction. Recent progress has been made to understand the origin of myofibroblasts by fate mapping; mechanisms and regulation of cell to cell interaction and communication within the heart and its constituent cells in cardiac fibrosis remain unclear.[6, 7] Better understanding of regulatory and mechanistic processes are important as they would provide direct therapeutic targets for modulation by drugs and/or antibody therapy in the prevention and treatment of end-organ damage
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