Abstract
Yes-associated protein (YAP) is an important regulator of cellular proliferation and transdifferentiation. However, little is known about the mechanisms underlying myofibroblast transdifferentiation in dilated cardiomyopathy (DCM). We investigated the role of YAP in the pathological process of cardiac matrix remodeling. A classic model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Cardiac fibroblasts were isolated from neonatal Sprague-Dawley rats by density gradient centrifugation. The expression levels of α-smooth muscle actin (α-SMA) and collagen volume fraction (CVF) were significantly increased in DCM mice. Angiotensin II (Ang II)-mediated YAP activation promoted the proliferation and transdifferentiation of neonatal rat cardiac fibroblasts, and this effect was significantly suppressed in the shRNA YAP + Ang II group compared with the shRNA Control + Ang II group in vitro (2.98±0.34 ×105 vs 5.52±0.82 ×105, P<0.01). Inhibition of endogenous Ang II-stimulated YAP improved the cardiac function by targeting myofibroblast transdifferentiation to attenuate matrix remodeling in vivo. In the valsartan group, left ventricular ejection fraction and fractional shortening were significantly increased compared with the DCM group (52.72±5.51% vs 44.46±3.01%, P<0.05; 34.84±3.85% vs 26.65±3.12%, P<0.01). Our study demonstrated that YAP was a regulator of cardiac myofibroblast differentiation, and regulation of YAP signaling pathway contributed to improve cardiac function of DCM mice, possibly in part by decreasing myofibroblast transdifferentiation to inhibit matrix remodeling.
Highlights
Dilated cardiomyopathy (DCM), characterized by a loss of cardiomyocytes and accumulation of extracellular matrix, is an important cause of congestive heart failure [1,2,3]
Immunofluorescence staining of a-smooth muscle actin (a-SMA) positive confirmed the transdifferentiation of cardiac myofibroblasts in the pathogenesis of DCM (Figure 1C)
To the best of our knowledge, this is the first time that Yes-associated protein (YAP) signaling pathway has been reported as the barrier to prevent the transdifferentiation of myofibroblasts in matrix remodeling of DCM
Summary
Dilated cardiomyopathy (DCM), characterized by a loss of cardiomyocytes and accumulation of extracellular matrix, is an important cause of congestive heart failure [1,2,3]. The exact mechanism of fibroblast transdifferentiation to myofibroblasts is still unclear. We explored the distinct role of Yes-associated protein (YAP) in the transdifferentiation of myofibroblasts during the pathological process of cardiac matrix remodeling. Hippo signaling pathway plays important roles in the control of organ size, tissue homeostasis, and regeneration, and dysregulation of the Hippo/YAP pathway can lead to uncontrolled cell growth and malignant transformation. We hypothesized that YAP signaling pathway is the barrier preventing the proliferation and transdifferentiation of cardiac fibroblasts.
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