1. Increased expression of adenosine triphosphate-sensitive K+ channels in mitral dysfunction: mechanically stimulated transcription and hypoxia-induced protein stability?
- Author
-
Raeis Dauvé, V., Philip Couderc, P., Faggian, Giuseppe, Tessari, Maddalena, Roatti, A., Milano, Aldo Domenico, Bochaton Piallat, M., and Baertschi, A. J.
- Subjects
Male ,Potassium Channels ,Myocardium/metabolism ,Messenger ,Blood Pressure ,Messenger/metabolism ,ddc:616.07 ,Mice ,Anoxia ,KATP Channels ,Anoxia/metabolism ,Hypoxia ,Kir6.2 expression ,Alpha Subunit/metabolism ,Mice, Knockout ,Mitral Valve Insufficiency/metabolism ,Protein Stability ,Mitral Valve Insufficiency ,Heart Ventricles/metabolism ,Middle Aged ,Inwardly Rectifying ,KATP Channels/metabolism ,Aged, Animals, Anoxia ,metabolism, Blood Gas Analysis, Blood Pressure, Echocardiography, Female, Gene Expression Regulation, Heart Ventricles ,metabolism, Humans, Hypoxia-Inducible Factor 1 ,alpha Subunit ,metabolism, KATP Channels ,metabolism, Male, Mice, Mice ,Knockout, Middle Aged, Mitral Valve Insufficiency ,metabolism, Myocardium ,metabolism, Oxygen ,physiology, Partial Pressure, Potassium Channels ,metabolism, Protein Stability, RNA ,metabolism, Stress ,Mechanical ,Echocardiography ,cardiovascular system ,Female ,Hypoxia-Inducible Factor 1 ,transcription ,endocrine system ,Heart Ventricles ,Knockout ,Partial Pressure ,Oxygen/physiology ,ischemia ,Stress ,Inwardly Rectifying/metabolism ,Animals ,Humans ,RNA, Messenger ,Potassium Channels, Inwardly Rectifying ,Aged ,Myocardium ,mechanical stress ,Hypoxia-Inducible Factor 1, alpha Subunit ,ddc:616.8 ,Oxygen ,Gene Expression Regulation ,physiology ,RNA ,Stress, Mechanical ,mitral regurgitation ,ddc:618.92 ,Blood Gas Analysis ,metabolism - Abstract
OBJECTIVES The aim of this study was to test whether adenosine triphosphate sensitive K(+) (KATP) channel expression relates to mechanical and hypoxic stress within the left human heart. BACKGROUND The KATP channels play a vital role in preserving the metabolic integrity of the stressed heart. However the mechanisms that govern the expression of their subunits (e.g. potassium inward rectifier [Kir] 6.2) in adult pathologies are mostly unknown. METHODS We collected biopsies from the 4 cardiac chambers and 50 clinical parameters from 30 surgical patients with severe mitral dysfunction. Proteins and messenger ribonucleic acids (mRNAs) of KATP pore subunits and mRNAs of their known transcriptional regulators (forkhead box [FOX] F2 FOXO1 FOXO3 and hypoxia inducible factor [HIF] 1a) were measured respectively by Western blotting immunohistochemistry and quantitative real time polymerase chain reaction and submitted to statistical analysis. RESULTS In all heart chambers Kir6.2 mRNA correlated with HIF 1a mRNA. Neither Kir6.1 nor Kir6.2 proteins positively correlated with their respective mRNAs. The HIF 1a mRNA related in the left ventricle to aortic pressure in the left atrium to left atrial pressure and in all heart chambers to a decreased Kir6.2 protein/mRNA ratio. Interestingly in the left heart Kir6.2 protein and its immunohistochemical detection in myocytes were maximal at low venous PO(2). In the left ventricle the Kir6.2 protein/mRNA ratio was also significantly higher at low venous PO(2) suggesting that tissue hypoxia might stabilize the Kir6.2 protein. CONCLUSIONS Results suggest that post transcriptional events determine Kir6.2 protein expression in the left ventricle of patients with severe mitral dysfunction and low venous PO(2). Mechanical stress mainly affects transcription of HIF 1a and Kir6.2. This study implies that new therapies could aim at the proteasome for stabilizing the left ventricular Kir6.2 protein.
- Published
- 2012