title: Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency.
abstract: Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction.
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Qin
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Chen
authors.initials: C
authors.lastname: Qu
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Huimei
authors.initials: H
authors.lastname: Zang
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Lei
authors.initials: L
authors.lastname: Qi
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Linmao
authors.initials: L
authors.lastname: Lyu
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Prakash
authors.initials: P
authors.lastname: Nagarkatti
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Janicki
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia. xingliwang@sdu.edu.cn Taixing.Cui@uscmed.sc.edu.
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University Qilu Hospital Research Center for Cell Therapy, Qilu Hospital of Shandong University, Shandong University School of Medicine, Jinan, Shandong, China (Q.Q., C.Q., T.N., H.Z., L.Q., L.L., X.L.W., T.C.); Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (X.W.); and Department of Pathology, Microbiology and Immunology (M.N., P.N.) and Department of Cell Biology and Anatomy (J.S.J., T.C.), University of South Carolina School of Medicine, Columbia. xingliwang@sdu.edu.cn Taixing.Cui@uscmed.sc.edu.
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction; D015854:Up-Regulation; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D051267:NF-E2-Related Factor 2
keywords: NF-E2-related factor 2; angiotensinogen; autophagy; myocardial infarction; ventricular remodeling