title: LRRC10 is required to maintain cardiac function in response to pressure overload.
abstract: We previously reported that the cardiomyocyte-specific leucine-rich repeat containing protein (LRRC)10 has critical functions in the mammalian heart. In the present study, we tested the role of LRRC10 in the response of the heart to biomechanical stress by performing transverse aortic constriction on Lrrc10-null (Lrrc10(-/-)) mice. Mild pressure overload induced severe cardiac dysfunction and ventricular dilation in Lrrc10(-/-) mice compared with control mice. In addition to dilation and cardiomyopathy, Lrrc10(-/-) mice showed a pronounced increase in heart weight with pressure overload stimulation and a more dramatic loss of cardiac ventricular performance, collectively suggesting that the absence of LRRC10 renders the heart more disease prone with greater hypertrophy and structural remodeling, although rates of cardiac fibrosis and myocyte dropout were not different from control mice. Lrrc10(-/-) cardiomyocytes also exhibited reduced contractility in response to β-adrenergic stimulation, consistent with loss of cardiac ventricular performance after pressure overload. We have previously shown that LRRC10 interacts with actin in the heart. Here, we show that His(150) of LRRC10 was required for an interaction with actin, and this interaction was reduced after pressure overload, suggesting an integral role for LRRC10 in the response of the heart to mechanical stress. Importantly, these experiments demonstrated that LRRC10 is required to maintain cardiac performance in response to pressure overload and suggest that dysregulated expression or mutation of LRRC10 may greatly sensitize human patients to more severe cardiac disease in conditions such as chronic hypertension or aortic stenosis.
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brody
authors.affiliation: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Grimes
authors.affiliation: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: Cardiovascular Genetics Research Laboratory and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.affiliation: Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Ravi C
authors.identifier: http://orcid.org/0000-0002-2473-950X
authors.initials: RC
authors.lastname: Balijepalli
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; youngsooklee@wisc.edu.
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Lee
mesh_terms: D000199:Actins / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D006332:Cardiomegaly / Q000503:physiopathology; D005355:Fibrosis / Q000473:pathology; D006321:Heart / Q000503:physiopathology*; D006331:Heart Diseases / Q000473:pathology; D006639:Histidine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000473:pathology; D011312:Pressure; D013312:Stress, Physiological; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D000199:Actins; D000318:Adrenergic beta-Agonists; D009124:Muscle Proteins; C482740:heart-restricted leucine-rich repeat protein, mouse; D006639:Histidine
keywords: cardiomyopathy; eccentric hypertrophy; leucine-rich repeat containing 10; pressure overload