Dan Lu1, Li Zhang1, Dan Bao1, Yingdong Lu1, Xu Zhang1, Ning Liu1, Wenping Ge1, Xiang Gao1, Hongliang Li2, Lianfeng Zhang3. 1. Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China. 2. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, China. 3. Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China. Electronic address: Zhanglf@cnilas.org.
Abstract
BACKGROUND: Calponin1 (CNN1) is involved in the regulation of smooth muscle contraction in physiological situation and it also expresses abnormally in a variety of pathological situations. We found that the expression of CNN1 decreased significantly in the heart tissue of a cTnT(R141W) transgenic dilated cardiomyopathy (DCM) mouse model and an adriamycin (ADR)-induced DCM mouse model, suggesting that CNN1 is involved in the pathogenesis of DCM. However, the role of CNN1 on cardiac function, especially on pathogenesis of DCM, has not been clarified. In this study, we tested whether rescued expression of CNN1 could prevent the development of DCM and investigated its possible mechanisms. METHODS AND RESULTS: The DCM phenotypes were significantly improved with the transgenic expression of CNN1 in the cTnT(R141W)×CNN1 double transgenic (DTG) mice, which was demonstrated by the survival, cardiac geometry and function analyses, as well as microstructural and ultrastructural observations based on echocardiography and histology examination. The expression of CNN1 could also resist the cardiac geometry breakage and dysfunction in the ADR-induced DCM mice model. Meanwhile, the epsilon isoform of protein kinase C (εPKC) activator and inhibitor could reverse the activation of εPKC/ERK/mTOR pathway and DCM phenotypes in the cTnT(R141W) and cTnT(R141W)×CNN1 double transgenic (DTG) mice. CONCLUSIONS: εPKC/ERK/mTOR pathway activation induced by the rescued expression of CNN1 contributed to the improvement of cardiac dysfunction and pathological changes observed in the DTG mice. CNN1 could be a therapeutic target to prevent the development of DCM and heart failure (HF).
BACKGROUND:Calponin1 (CNN1) is involved in the regulation of smooth muscle contraction in physiological situation and it also expresses abnormally in a variety of pathological situations. We found that the expression of CNN1 decreased significantly in the heart tissue of a cTnT(R141W) transgenic dilated cardiomyopathy (DCM) mouse model and an adriamycin (ADR)-induced DCMmouse model, suggesting that CNN1 is involved in the pathogenesis of DCM. However, the role of CNN1 on cardiac function, especially on pathogenesis of DCM, has not been clarified. In this study, we tested whether rescued expression of CNN1 could prevent the development of DCM and investigated its possible mechanisms. METHODS AND RESULTS: The DCM phenotypes were significantly improved with the transgenic expression of CNN1 in the cTnT(R141W)×CNN1 double transgenic (DTG) mice, which was demonstrated by the survival, cardiac geometry and function analyses, as well as microstructural and ultrastructural observations based on echocardiography and histology examination. The expression of CNN1 could also resist the cardiac geometry breakage and dysfunction in the ADR-induced DCMmice model. Meanwhile, the epsilon isoform of protein kinase C (εPKC) activator and inhibitor could reverse the activation of εPKC/ERK/mTOR pathway and DCM phenotypes in the cTnT(R141W) and cTnT(R141W)×CNN1 double transgenic (DTG) mice. CONCLUSIONS: εPKC/ERK/mTOR pathway activation induced by the rescued expression of CNN1 contributed to the improvement of cardiac dysfunction and pathological changes observed in the DTGmice. CNN1 could be a therapeutic target to prevent the development of DCM and heart failure (HF).
Authors: Zhiping Cao; Jessica Minnier; Lijuan Liu; Kristin L Lyon Scott; Ashok P Reddy; Phillip A Wilmarth; Larry L David; Anthony P Barnes; Marjorie R Grafe; Sanjiv Kaul; Nabil J Alkayed; Catherine M Davis Journal: Sci Rep Date: 2022-05-25 Impact factor: 4.996
Authors: Michael J Bround; Rich Wambolt; Haoning Cen; Parisa Asghari; Razvan F Albu; Jun Han; Donald McAfee; Marc Pourrier; Nichollas E Scott; Lubos Bohunek; Jerzy E Kulpa; S R Wayne Chen; David Fedida; Roger W Brownsey; Christoph H Borchers; Leonard J Foster; Thibault Mayor; Edwin D W Moore; Michael F Allard; James D Johnson Journal: J Biol Chem Date: 2016-09-12 Impact factor: 5.157