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J Thorac Cardiovasc Surg 2008;136:709-716
© 2008 The American Association for Thoracic Surgery

Evolving Technology

Induction by left ventricular overload and left ventricular failure of the human Jumonji gene (JARID2) encoding a protein that regulates transcription and reexpression of a protective fetal program

Esta Bovill, MBBSa,*, Stephen Westaby, MS PhDb, Shiney Reji, PhDa, Rana Sayeed, MDb, Alastair Crisp, MAc, Tony Shaw, PhDa

a Department of Medicine, University College London, London, UK
b John Radcliffe Hospital, Oxford, UK
c Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK

Received for publication August 19, 2007; revisions received January 23, 2008; accepted for publication February 15, 2008.

* Address for reprints: Esta Bovill, MBBS, c/o Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. (Email: ebovill{at}doctors.net.uk).

Objective: We identified changes in Jumonji (JARID2) expression in failing human hearts and determined its effects on expressions of atrial natriuretic factor (ANF), myosin light chain 2a (MLC2A), and {alpha} myosin heavy chain (MHCA), genes associated with both human heart failure and the fetal gene program.

Methods: Left ventricular outflow tract cardiac biopsy samples were taken from 31 patients with aortic valvular stenosis. Hearts were grouped according to left ventricular size and function: nonfailing hearts (undilated with good function) and failing hearts (dilated with poor function). Protein levels were determined by Western blotting, and messenger RNA transcript levels by ratiometric reverse transcriptase–polymerase chain reaction. Luciferase assays in HL-2 cells were used to assess effects of Jarid2 on Anf, Mlc2a, and Mhca transcriptions. Chromatin immunoprecipitation was used to detect interaction of JARID2 with specific target-gene promoters.

Results: JARID2 and MHCA expressions were reduced in failing hearts, whereas MLC2A and ANF were increased. In HL-2 cell culture, Jarid2 suppressed Anf and Mlc2a but enhanced Mhca. Jarid2 expression was reduced by cyclic mechanical stress, with concomitant increased Anf and Mlc2a and decreased Mhca expressions, reproducing the expression profile found in decompensated human pressure overload.

Conclusion: Jumonji expression is reduced by mechanical stress in human heart failure from aortic stenosis. JARID2 regulates ANF, MLC2A, and MHCA transcription and contributes to reexpression of the fetal gene program in decompensated aortic stenosis. JARID2 appears important in transcriptional regulation of fetal genes and may emerge as a diagnostic marker for left ventricular decompensation in aortic stenosis.

Abbreviations and Acronyms {alpha}-MHC = {alpha} myosin heavy chain; ANF = atrial natriuretic factor; ANF = human gene for atrial natriuretic factor; Anf = mouse gene for atrial natriuretic factor; β-MHC = β myosin heavy chain; bp = base pairs; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; GFP = green fluorescent protein; JARID2 = human Jumonji gene; Jarid2 = mouse Jumonji gene; kb = kilobase; LV = left ventricle; LVEF = left ventricular ejection fraction; MHCA = human gene for {alpha} myosin heavy chain; Mhca = mouse gene for {alpha} myosin heavy chain; MLC-2 = myosin light chain 2; MLC2A = human gene for myosin light chain 2a; Mlc2a = mouse gene for myosin light chain 2a; mRNA = messenger RNA; PCR = polymerase chain reaction; RT-PCR = reverse transcriptase–polymerase chain reaction






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