title: Knockout of the Na,K-ATPase α2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction.
abstract: The α2-isoform of the Na,K-ATPase (α2) is the minor isoform of the Na,K-ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing α2 that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of α2 to further define the tissue-specific role of α2 in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of α2 in the heart using β-myosin heavy chain Cre. We have achieved a 90% knockout of α2 expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post-transverse aortic constriction. These results suggest that heart expression of α2 does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of α2 plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of α2 determines its unique roles in the regulation of cardiovascular function.
authors: Department of Molecular Genetics, Biochemistry, and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors: Tara N
authors: TN
authors: Rindler
authors: Valerie M
authors: VM
authors: Lasko
authors: Michelle L
authors: ML
authors: Nieman
authors: Motoi
authors: M
authors: Okada
authors: John N
authors: JN
authors: Lorenz
authors: Jerry B
authors: JB
authors: Lingrel
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000009:adverse effects*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D055786:Gene Knockout Techniques / Q000379:methods; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D019426:Integrases; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000502:physiology*; D014463:Ultrasonography; D014661:Vasoconstriction; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*
chemical_list: C551613:Myh7 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D000324:Adrenocorticotropic Hormone; C045073:Cre recombinase; D019426:Integrases; C401838:Atp1a2 protein, mouse; D018995:Myosin Heavy Chains; D000254:Sodium-Potassium-Exchanging ATPase