Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency

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.

[1]  R. Gottlieb,et al.  This old heart: Cardiac aging and autophagy. , 2015, Journal of molecular and cellular cardiology.

[2]  H. Watada,et al.  Minireview: Autophagy in pancreatic β-cells and its implication in diabetes. , 2015, Molecular endocrinology.

[3]  Shukun Wang,et al.  Autophagy‐related gene Atg5 is essential for astrocyte differentiation in the developing mouse cortex , 2014, EMBO reports.

[4]  J. Ingelfinger,et al.  Catalase Overexpression Prevents Nuclear Factor Erythroid 2–Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression, Hypertension, and Kidney Injury in Diabetic Mice , 2014, Diabetes.

[5]  J. S. Janicki,et al.  Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins. , 2014, Journal of molecular and cellular cardiology.

[6]  Jinbao Liu,et al.  Autophagic-Lysosomal Inhibition Compromises Ubiquitin-Proteasome System Performance in a p62 Dependent Manner in Cardiomyocytes , 2014, PloS one.

[7]  Zhonglin Xie,et al.  The interplay between autophagy and apoptosis in the diabetic heart. , 2014, Journal of molecular and cellular cardiology.

[8]  B. Li,et al.  Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction , 2014, Oxidative medicine and cellular longevity.

[9]  Joseph A. Hill,et al.  Enhanced autophagy ameliorates cardiac proteinopathy. , 2013, The Journal of clinical investigation.

[10]  G. Lopaschuk,et al.  Impact of the renin-angiotensin system on cardiac energy metabolism in heart failure. , 2013, Journal of molecular and cellular cardiology.

[11]  A. Gomes,et al.  Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy. , 2013, Cardiovascular research.

[12]  B. K. Park,et al.  The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. , 2013, Biochemical pharmacology.

[13]  Masaaki Komatsu,et al.  Keap1 degradation by autophagy for the maintenance of redox homeostasis , 2012, Proceedings of the National Academy of Sciences.

[14]  J. S. Janicki,et al.  Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. , 2011, Cardiovascular research.

[15]  S. Reddy,et al.  CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs. , 2010, The Journal of clinical investigation.

[16]  K. Itoh,et al.  Discovery of the negative regulator of Nrf2, Keap1: a historical overview. , 2010, Antioxidants & redox signaling.

[17]  M. McMahon,et al.  p62/SQSTM1 Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription* , 2010, The Journal of Biological Chemistry.

[18]  Mihee M. Kim,et al.  The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 , 2010, Nature Cell Biology.

[19]  N. Mizushima,et al.  Methods in Mammalian Autophagy Research , 2010, Cell.

[20]  J. S. Janicki,et al.  Nrf2 Protects Against Maladaptive Cardiac Responses to Hemodynamic Stress , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[21]  Y. Pinto,et al.  Avoidance of Transient Cardiomyopathy in Cardiomyocyte-Targeted Tamoxifen-Induced MerCreMer Gene Deletion Models , 2009, Circulation research.

[22]  J. S. Janicki,et al.  Targeting the Nrf2 pathway against cardiovascular disease , 2009, Expert opinion on therapeutic targets.

[23]  M. Sporn,et al.  Targeting Nrf2 with the triterpenoid CDDO- imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice , 2009, Proceedings of the National Academy of Sciences.

[24]  Chengqun Huang,et al.  A method to measure cardiac autophagic flux in vivo , 2008, Autophagy.

[25]  M. Periasamy,et al.  Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. , 2007, Cardiovascular research.

[26]  T. Hewett,et al.  Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. , 2007, The Journal of clinical investigation.

[27]  S. Odelberg,et al.  Human αB-Crystallin Mutation Causes Oxido-Reductive Stress and Protein Aggregation Cardiomyopathy in Mice , 2007, Cell.

[28]  Abhinav K. Jain,et al.  GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. , 2007, The Journal of biological chemistry.

[29]  Yasushi Matsumura,et al.  The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress , 2007, Nature Medicine.

[30]  Shyam Biswal,et al.  Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. , 2007, Annual review of pharmacology and toxicology.

[31]  L. Tecott,et al.  Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload. , 2006, The Journal of clinical investigation.

[32]  E. Olson,et al.  Toward transcriptional therapies for the failing heart: chemical screens to modulate genes. , 2005, The Journal of clinical investigation.

[33]  E. Hirsch,et al.  Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence. , 2004, Cardiovascular research.

[34]  G. Booz,et al.  Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure. , 2002, Journal of molecular and cellular cardiology.

[35]  T. Hewett,et al.  Expression of R120G–αB-Crystallin Causes Aberrant Desmin and αB-Crystallin Aggregation and Cardiomyopathy in Mice , 2001 .

[36]  T. Hewett,et al.  Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. , 2001, Circulation research.

[37]  L. Mazzolai,et al.  Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice. , 2000, Hypertension.

[38]  S. O. Kim,et al.  A Catalytically Active Jak2 Is Required for the Angiotensin II-dependent Activation of Fyn* , 1999, The Journal of Biological Chemistry.

[39]  H. Drexler,et al.  The renin-angiotensin system and experimental heart failure. , 1999, Cardiovascular research.

[40]  L. Mazzolai,et al.  Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. , 1998, Hypertension.