PMID:19920172

Citation	Zhao, W, Waggoner, JR, Zhang, ZG, Lam, CK, Han, P, Qian, J, Schroder, PM, Mitton, B, Kontrogianni-Konstantopoulos, A, Robia, SL and Kranias, EG (2009) The anti-apoptotic protein HAX-1 is a regulator of cardiac function. Proc. Natl. Acad. Sci. U.S.A. 106:20776-81
Abstract	The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed protein that protects cardiomyocytes from programmed cell death. Here we identify HAX-1 as a regulator of contractility and calcium cycling in the heart. HAX-1 overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity in isolated cardiomyocytes and in vivo, leading to depressed myocyte calcium kinetics and mechanics. Conversely, downregulation of HAX-1 enhanced calcium cycling and contractility. The inhibitory effects of HAX-1 were abolished upon phosphorylation of phospholamban, which plays a fundamental role in controlling basal contractility and constitutes a key downstream effector of the beta-adrenergic signaling cascade. Mechanistically, HAX-1 promoted formation of phospholamban monomers, the active/inhibitory units of the calcium pump. Indeed, ablation of PLN rescued HAX-1 inhibition of contractility in vivo. Thus, HAX-1 represents a regulatory mechanism in cardiac calcium cycling and its responses to sympathetic stimulation, implicating its importance in calcium homeostasis and cell survival.
Links	PubMed PMC2791603 Online version:10.1073/pnas.0906998106
Keywords	Aging/metabolism; Animals; Apoptosis; Biological Transport; Calcium/metabolism; Calcium-Binding Proteins/deficiency; Calcium-Binding Proteins/metabolism; Down-Regulation; Fluorescence Resonance Energy Transfer; Heart/physiology; Heart Function Tests; Mice; Mice, Transgenic; Myocardial Contraction/physiology; Myocytes, Cardiac/cytology; Myocytes, Cardiac/metabolism; Organ Specificity; Protein Binding; Proteins/metabolism; Rats; Sarcoplasmic Reticulum/metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism; Transgenes
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:HAX1	part_of	GO:0016529: sarcoplasmic reticulum	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:HAX1		GO:0016529: sarcoplasmic reticulum	ECO:0000314:		C		Figure 1 shows HAX-1 overexpression or downregulation effects on on rat cardiomyocyte contractile function.	complete CACAO 6417
MOUSE:HAX1		GO:0016529: sarcoplasmic reticulum	ECO:0000314:		C		Figure 2 shows the effects of cardiac-specific HAX-1 overexpressing in mice.	complete CACAO 6419
MOUSE:HAX1	part_of	GO:0016529: sarcoplasmic reticulum	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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