The anti-apoptotic protein HAX-1 is a regulator of cardiac function.
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.
Zhao
Wen
W
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
Waggoner
Jason R
JR
Zhang
Zhi-Guo
ZG
Lam
Chi Keung
CK
Han
Peidong
P
Qian
Jiang
J
Schroder
Paul M
PM
Mitton
Bryan
B
Kontrogianni-Konstantopoulos
Aikaterini
A
Robia
Seth L
SL
Kranias
Evangelia G
EG
D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D015536:Down-Regulation; D031541:Fluorescence Resonance Energy Transfer; D006321:Heart / Q000502:physiology*; D006334:Heart Function Tests; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019076:Transgenes; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C491295:Hs1bp1 protein, mouse