Histidine-rich Ca binding protein: a regulator of sarcoplasmic reticulum calcium sequestration and cardiac function.
Defects in the pathways that regulate cardiac sarcoplasmic reticulum (SR) calcium (Ca) cycling represent prime targets for driving the deterioration of function and progression to heart failure. We hypothesized that the histidine-rich Ca binding protein (HRC) in the SR may be involved in SR Ca cycling and that alterations in HRC levels would result in abnormal cardiac Ca homeostasis. In order to test this hypothesis, we generated transgenic mice with cardiac overexpression (3-fold) of HRC. Increased cardiac HRC levels were associated with impaired SR Ca uptake rates (35%) and attenuated cardiomyocyte Ca transient decay (38%), without alterations in peak Ca transients or SR Ca load. The depressed SR Ca sequestration was associated with attenuated rate of Ca extrusion via Na-Ca exchange. Triadin protein expression levels and L-type Ca channel current density were increased, while the channel inactivation kinetics were not altered. Impaired SR Ca uptake and delayed Ca decline rates triggered hypertrophy and compromised the heart's responses to increased stress by either hemodynamic overload or the aging process. By 18 months of age, cardiac remodeling deteriorated to congestive heart failure in transgenic mice. Collectively, these data suggest that HRC may be an integral regulatory protein involved in cardiac muscle SR Ca uptake and Ca homeostasis.
Gregory
Kimberly N
KN
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575, USA.
Ginsburg
Kenneth S
KS
Bodi
Ilona
I
Hahn
Harvey
H
Marreez
Yehia M A
YM
Song
Qiujing
Q
Padmanabhan
Prabhu A
PA
Mitton
Bryan A
BA
Waggoner
Jason R
JR
Del Monte
Federica
F
Park
Woo Jin
WJ
Dorn
Gerald W
GW
Bers
Donald M
DM
Kranias
Evangelia G
EG
D000818:Animals; D001011:Aorta / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006321:Heart / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; C489418:Hrc protein, mouse; D002118:Calcium