HAX-1 regulates SERCA2a oxidation and degradation

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.

Phospholamban and sarcolipin prevent thermal inactivation of sarco(endo)plasmic reticulum Ca2+-ATPases

“…Our finding that PLN ablation increases susceptibility to thermal inactivation of SERCA2a in mouse cardiac tissue is consistent with an increased susceptibility to ischemic cardiac injury in those animals [32]. Furthermore, the cardiac-specific ablation of the anti-apoptotic protein HAX-1, decreases PLN binding to SERCA2a [58] and increases SERCA2a oxidation and degradation and susceptibility to ischemic cardiac injury [59], whereas over-expression of HAX-1 protects against ischemic injury [60].…”

MicroRNA‑125a‑5p regulates liver cancer cell growth, migration and invasion and EMT by targeting HAX1

“…Hematopoietic cell-specific protein 1-associated protein X-1 (HAX1) is a multifunctional protein ~35 kda in size and is involved in anti-apoptosis, migration, adhesion and endocytosis regulation (9)(10)(11). A previous study found that highly-expressed HAX1 is associated with poor survival in human colorectal cancer (12), cutaneous squamous cell carcinoma (13), laryngeal carcinoma (14) and multiple myeloma (15).…”

The YAP/SERCA2a signaling pathway protects cardiomyocytes against reperfusion-induced apoptosis

“…In the present study, we report that SERCA2a is transcriptionally regulated by YAP, such that reduced levels of YAP cause SERCA2a downregulation in I/R-treated cardiomyocytes. In addition, a recent study has reported that HAX-1 regulates post-transcriptional modifications, including oxidation and degradation, of SERCA2a in cardiomyocytes [ 46 ]. SERCA2a downregulation or inactivation is closely associated with myocardial infarction [ 47 ], atrial arrhythmias [ 48 ], hypertension [ 49 ], cardiac aging [ 50 ], heart failure [ 51 ], and myocardial hypertrophy [ 52 ].…”