title: Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.
abstract: The mechanisms linking the expression of sarcomeric mutant proteins to the development of pathological hypertrophy in hypertrophic cardiomyopathy (HCM) remain poorly understood. We investigated the role of the plasma membrane Ca(2+)-ATPase PMCA4 in the HCM phenotype using a transgenic model that expresses mutant (Glu180Gly) α-tropomyosin (Tm180) in heart. Immunoblot analysis revealed that cardiac PMCA4 expression was upregulated early in Tm180 disease pathogenesis. This was accompanied by an increase in levels of the L-type Ca(2+)-channel, which is implicated in pathological hypertrophy. When Tm180 mice were crossed with a PMCA4-null line, loss of PMCA4 caused the abrogation of hypertrophy in Tm180/PMCA4-null double mutant mice. RT-PCR analysis of Tm180/PMCA4-null hearts revealed blunting of the fetal program and reversion of pro-fibrotic Col1a1 and Col3a1 gene expression to wild-type levels. This was accompanied by evidence of reduced L-type Ca(2+)-channel expression, and diminished calcineurin activity. Expression of the metabolic substrate transporters glucose transporter 4 and carnitine palmitoyltransferase 1b was preserved and Tm180-related changes in mRNA levels of various contractile stress-related proteins including the cardiac ankyrin protein CARP and the N2B isoform of titin were reversed in Tm180/PMCA4-null hearts. cGMP levels were increased and phosphorylation of vasodilator-stimulated phosphoprotein was elevated in Tm180/PMCA4-null hearts. These changes were associated with a sharp reduction in left ventricular end-diastolic pressure in Tm180/PMCA4-null hearts, which occurred despite persistence of Tm180-related impairment of relaxation dynamics. These results reveal a novel and specific role for PMCA4 in the Tm180 hypertrophic phenotype, with the "protective" effects of PMCA4 deficiency encompassing multiple determinants of HCM-related hypertrophy.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: prasad.vikram@gmail.com.
authors.forename: Vikram
authors.initials: V
authors.lastname: Prasad
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Lasko
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Nieman
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Rubinstein
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006339:Heart Rate; D008297:Male; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism; D017725:Ventricular Pressure
chemical_list: C490774:Tpm1 protein, mouse; D014335:Tropomyosin; D053499:Plasma Membrane Calcium-Transporting ATPases
keywords: Diastolic dysfunction; Diastolic properties; Hypertrophic cardiomyopathy; PMCA4; Pathological hypertrophy; Ventricular stiffness