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.
Subject(s)
Animals , Male , Rats , Angiotensin II/pharmacology , Cardiomyopathy, Dilated/physiopathology , Adaptor Proteins, Signal Transducing/drug effects , Cell Transdifferentiation/drug effects , Myofibroblasts/drug effects , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/physiology , Swine , Echocardiography , Cardiomyopathy, Dilated/pathology , Cell Differentiation , Blotting, Western , Rats, Sprague-Dawley , Cell Cycle Proteins , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/physiology , Disease Models, Animal , Myofibroblasts/physiology , Mice, Inbred BALB C , Microscopy, FluorescenceABSTRACT
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.
Subject(s)
Adaptor Proteins, Signal Transducing/drug effects , Angiotensin II/pharmacology , Cardiomyopathy, Dilated/physiopathology , Cell Transdifferentiation/drug effects , Myofibroblasts/drug effects , Phosphoproteins/drug effects , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/physiology , Animals , Blotting, Western , Cardiomyopathy, Dilated/pathology , Cell Cycle Proteins , Cell Differentiation , Disease Models, Animal , Echocardiography , Male , Mice , Mice, Inbred BALB C , Microscopy, Fluorescence , Myofibroblasts/physiology , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/physiology , Rats , Rats, Sprague-Dawley , Swine , YAP-Signaling ProteinsABSTRACT
Red mud storage facility (RM-SF) pollution remains a serious problem in China mainly due to the RM's huge quantity, little recyclability, and high alkalinity. And, there is also a risk of dam failure because almost all RM-SFs are processed by damming. In order to address this challenge and improve the level of risk management, it is necessary to evaluate the environmental risk of RM-SFs systematically. So, this paper firstly designs a comprehensive evaluation index system with a three-level evaluation index in the terms of RM characteristics, RM-SF characteristics, ambient environment of RM-SF, the management of RM-SF, and the application aspect of RM by the analytic hierarchy process (AHP) method. Then, a case of RM-SF from a typical alumina production enterprise is studied according to this system, as is assisted by several experts from different fields when determining the weights of all indicators. The results show that the risk of selected RM-SF primarily depends on the former factors, that is, RM and RM-SF characteristics, while the contributions of the other factors are quite smaller.
