Changes in gene expression in the intact human heart: Downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium

Brian D. Lowes, Wayne Minobe, William T. Abraham, Mona N. Rizeq, Teresa J. Bohlmeyer, Robert A. Quaife, Robert L. Roden, Darrin L. Dutcher, Alastair O. Robertson, Norbert F. Voelkel, David B. Badesch, Bertron M. Groves, Edward M. Gilbert, Michael R. Bristow

Research output: Contribution to journalArticle

369 Citations (Scopus)

Abstract

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of β1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of β2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of α-myosin heavy chain mRNA (α-MHC, 23-34% of total), and (b) in heart failure α-MHC was down-regulated (by 67-84%) and β-MHC gene expression was up-regulated. We conclude that at the mRNA level nonfailing human heart expresses substantial α-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

Original languageEnglish (US)
Pages (from-to)2315-2324
Number of pages10
JournalJournal of Clinical Investigation
Volume100
Issue number9
DOIs
StatePublished - Nov 1 1997

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Myosin Heavy Chains
Dilated Cardiomyopathy
Myocardium
Down-Regulation
Gene Expression
Messenger RNA
Hypertrophy
Up-Regulation
Heart Failure
Atrial Natriuretic Factor
Heart Transplantation
Myosins
Muscle Cells
Protein Isoforms
Proteins
RNA
Phenotype
Biopsy
Polymerase Chain Reaction
Familial Primary Pulmonary Hypertension

Keywords

  • Atrial natriuretic peptide
  • Sarcoplasmic reticulum Ca ATPase
  • α-myosin heavy chain
  • β-adrenergic receptors
  • β-myosin heavy chain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Changes in gene expression in the intact human heart : Downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium. / Lowes, Brian D.; Minobe, Wayne; Abraham, William T.; Rizeq, Mona N.; Bohlmeyer, Teresa J.; Quaife, Robert A.; Roden, Robert L.; Dutcher, Darrin L.; Robertson, Alastair O.; Voelkel, Norbert F.; Badesch, David B.; Groves, Bertron M.; Gilbert, Edward M.; Bristow, Michael R.

In: Journal of Clinical Investigation, Vol. 100, No. 9, 01.11.1997, p. 2315-2324.

Research output: Contribution to journalArticle

Lowes, BD, Minobe, W, Abraham, WT, Rizeq, MN, Bohlmeyer, TJ, Quaife, RA, Roden, RL, Dutcher, DL, Robertson, AO, Voelkel, NF, Badesch, DB, Groves, BM, Gilbert, EM & Bristow, MR 1997, 'Changes in gene expression in the intact human heart: Downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium', Journal of Clinical Investigation, vol. 100, no. 9, pp. 2315-2324. https://doi.org/10.1172/JCI119770
Lowes, Brian D. ; Minobe, Wayne ; Abraham, William T. ; Rizeq, Mona N. ; Bohlmeyer, Teresa J. ; Quaife, Robert A. ; Roden, Robert L. ; Dutcher, Darrin L. ; Robertson, Alastair O. ; Voelkel, Norbert F. ; Badesch, David B. ; Groves, Bertron M. ; Gilbert, Edward M. ; Bristow, Michael R. / Changes in gene expression in the intact human heart : Downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium. In: Journal of Clinical Investigation. 1997 ; Vol. 100, No. 9. pp. 2315-2324.
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abstract = "Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of β1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of β2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of α-myosin heavy chain mRNA (α-MHC, 23-34{\%} of total), and (b) in heart failure α-MHC was down-regulated (by 67-84{\%}) and β-MHC gene expression was up-regulated. We conclude that at the mRNA level nonfailing human heart expresses substantial α-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.",
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T1 - Changes in gene expression in the intact human heart

T2 - Downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium

AU - Lowes, Brian D.

AU - Minobe, Wayne

AU - Abraham, William T.

AU - Rizeq, Mona N.

AU - Bohlmeyer, Teresa J.

AU - Quaife, Robert A.

AU - Roden, Robert L.

AU - Dutcher, Darrin L.

AU - Robertson, Alastair O.

AU - Voelkel, Norbert F.

AU - Badesch, David B.

AU - Groves, Bertron M.

AU - Gilbert, Edward M.

AU - Bristow, Michael R.

PY - 1997/11/1

Y1 - 1997/11/1

N2 - Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of β1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of β2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of α-myosin heavy chain mRNA (α-MHC, 23-34% of total), and (b) in heart failure α-MHC was down-regulated (by 67-84%) and β-MHC gene expression was up-regulated. We conclude that at the mRNA level nonfailing human heart expresses substantial α-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

AB - Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of β1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of β2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of α-myosin heavy chain mRNA (α-MHC, 23-34% of total), and (b) in heart failure α-MHC was down-regulated (by 67-84%) and β-MHC gene expression was up-regulated. We conclude that at the mRNA level nonfailing human heart expresses substantial α-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

KW - Atrial natriuretic peptide

KW - Sarcoplasmic reticulum Ca ATPase

KW - α-myosin heavy chain

KW - β-adrenergic receptors

KW - β-myosin heavy chain

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