title: Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins.
abstract: Nuclear factor erythroid-2 related factor 2 (Nrf2) is a master transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes. While knockout of Nrf2 exaggerates cardiac pathological remodeling and dysfunction in diverse pathological settings, pharmacological activation of Nrf2 protects against cardiomyocyte injury and cardiac dysfunction. In contrast, there is also a concern that the chronic activation of Nrf2 secondary to oxidative stress is a contributing mechanism for the reductive stress-mediated heart failure. However, a direct link between cardiac specific activation of Nrf2 and cardiac protection or dysfunction in vivo remains to be established. Therefore, we investigated the effect of cardiomyocyte-specific transgenic activation of Nrf2 (Nrf2(ctg)) on cardiac pathological remodeling and dysfunction. We found that the cardiomyocyte-specific activation of Nrf2 suppressed myocardial oxidative stress as well as cardiac apoptosis, fibrosis, hypertrophy, and dysfunction in a setting of sustained pressure overload induced by transverse aortic arch constriction (TAC) in mice. Notably, the constitutive activation of Nrf2 increased the steady level of autophagosomes while decreasing the ubiquitinated protein aggregates in the heart after TAC. Nrf2 gene gain- and loss-of-function approaches revealed that Nrf2 enhances autophagosome formation and autophagic flux in cardiomyocytes. Unexpectedly, while Nrf2 minimally regulated apoptosis, it suppressed significantly the proteotoxic necrosis in cardiomyocytes. In addition, Nrf2 attenuated the proteocytotoxicity presumably via enhancing autophagy-mediated clearance of ubiquitinated protein aggregates in cardiomyocytes. Taken together, we demonstrated for the first time that cardiac specific activation of Nrf2 suppresses cardiac maladaptive remodeling and dysfunction most likely by enhancing autophagic clearance of toxic protein aggregates in the heart.
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Siying
authors.initials: S
authors.lastname: Li
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Yimu
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, SC 29208, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Horvath
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, SC 29208, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Janicki
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA. Electronic address: Dongqi.Tang@uscmed.sc.edu.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina, SC 29208, USA. Electronic address: Taixing.Cui@uscmed.sc.edu.
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D066263:Protein Aggregation, Pathological; D059748:Proteolysis; D051381:Rats; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D025801:Ubiquitin; D057149:Ubiquitinated Proteins
keywords: Autophagy; Cardiac dysfunction; Necrosis; Nrf2; Oxidative stress; Proteinopathy
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