@article {26564,
	title = {HAX-1 regulates SERCA2a oxidation and degradation},
	journal = {J Mol Cell CardiolJ Mol Cell CardiolJ Mol Cell Cardiol},
	volume = {114},
	year = {2018},
	note = {Bidwell, Philip ALiu, Guan-ShengNagarajan, NarayaniLam, Chi KeungHaghighi, KobraGardner, GeorgeCai, Wen-FengZhao, WenMugge, LukeVafiadaki, ElizabethSanoudou, DespinaRubinstein, JackLebeche, DjamelHajjar, RogerSadoshima, JunichiKranias, Evangelia GengR01 HL026057/HL/NHLBI NIH HHS/R01 HL064018/HL/NHLBI NIH HHS/R01 HL129814/HL/NHLBI NIH HHS/T32 HL125204/HL/NHLBI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tEngland2017/11/25 06:00J Mol Cell Cardiol. 2018 Jan;114:220-233. doi: 10.1016/j.yjmcc.2017.11.014. Epub 2017 Nov 21.},
	month = {Jan},
	pages = {220-233},
	abstract = {Ischemia/reperfusion injury is associated with contractile dysfunction and increased cardiomyocyte death. Overexpression of the hematopoietic lineage substrate-1-associated protein X-1 (HAX-1) has been shown to protect from cellular injury but the function of endogenous HAX-1 remains obscure due to early lethality of the knockout mouse. Herein we generated a cardiac-specific and inducible HAX-1 deficient model, which uncovered an unexpected role of HAX-1 in regulation of sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) in ischemia/reperfusion injury. Although ablation of HAX-1 in the adult heart elicited no morphological alterations under non-stress conditions, it diminished contractile recovery and increased infarct size upon ischemia/reperfusion injury. These detrimental effects were associated with increased loss of SERCA2a. Enhanced SERCA2a degradation was not due to alterations in calpain and calpastatin levels or calpain activity. Conversely, HAX-1 overexpression improved contractile recovery and maintained SERCA2a levels. The regulatory effects of HAX-1 on SERCA2a degradation were observed at multiple levels, including intact hearts, isolated cardiomyocytes and sarcoplasmic reticulum microsomes. Mechanistically, HAX-1 ablation elicited increased production of reactive oxygen species at the sarco/endoplasic reticulum compartment, resulting in SERCA2a oxidation and a predisposition to its proteolysis. This effect may be mediated by NAPDH oxidase 4 (NOX4), a novel binding partner of HAX-1. Accordingly, NOX inhibition with apocynin abrogated the effects of HAX-1 ablation in hearts subjected to ischemia/reperfusion injury. Taken together, our findings reveal a role of HAX-1 in the regulation of oxidative stress and SERCA2a degradation, implicating its importance in calcium homeostasis and cell survival pathways.},
	keywords = {*Proteolysis, Adaptor Proteins, Signal Transducing/genetics/*metabolism, Aged, Animals, Calpain/metabolism, Endoplasmic Reticulum/metabolism, Female, Gene Deletion, Heart Failure/genetics/pathology/physiopathology, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Inbred C57BL, Middle Aged, Myocardial Contraction, Myocardial Reperfusion Injury/pathology/physiopathology, Myocardium/pathology, Myocytes, Cardiac/metabolism, NADPH Oxidase 4/metabolism, Oxidation-Reduction, Oxidative Stress, Proteins/*metabolism, Rats, Wistar, Reactive Oxygen Species/metabolism, Recovery of Function, RNA, Messenger/genetics/metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism, Sarcoplasmic Reticulum/metabolism},
	isbn = {1095-8584 (Electronic)0022-2828 (Linking)},
	author = {Bidwell, P. A. and Liu, G. S. and Nagarajan, N. and Lam, C. K. and Haghighi, K. and Gardner, G. and Cai, W. F. and Zhao, W. and Mugge, L. and Vafiadaki, E. and Sanoudou, D. and Rubinstein, J. and Lebeche, D. and Hajjar, R. and Sadoshima, J. and Kranias, EG}
}
