Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure: Marked upregulation of genes encoding extracellular matrix components

Marvin O. Boluyt, Lydia O'Neill, Andrea L. Meredith, Oscar H.L. Bing, Wesley W. Brooks, Chester H. Conrad, Michael T. Crow, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review

Abstract

The failing heart is characterized by impaired cardiac muscle function and increased interstitial fibrosis. Our purpose was to determine whether the functional impairment of the failing heart is associated with changes in levels of mRNA encoding proteins that modulate parameters of contraction and relaxation and whether the increased fibrosis observed in the failing heart is related to elevated expression of genes encoding extracellular matrix components. We studied hearts of 18- to 24-month-old spontaneously hypertensive rats with signs and symptoms of heart failure (SHR-F) or without evidence of failure (SHR-NF) and of age-matched normotensive Wistar-Kyoto (WKY) rats. Compared with WKY rats, SHR-NF exhibited left ventricular (LV) hypertrophy (2.2-fold) and right ventricular (RV) hypertrophy (1.5-fold), whereas SHR-F were characterized by comparable LV hypertrophy (2.1-fold) and augmented RV hypertrophy (2.4-fold; all P<.01). Total RNA was isolated from ventricles and subjected to Northern blot analysis. In SHR-F hearts, the level of α-myosin heavy chain mRNA was decreased in both ventricles to 1/3 and 1/5 of the SHR-NF and WKY values, respectively (both P<.01). Levels of β-myosin heavy chain, α-cardiac actin, and myosin light chain-2 mRNAs were not significantly altered in hearts of SHR-NF or SHR-F. Levels of α- skeletal actin were twofold greater in SHR-NF hearts compared with WKY hearts and were intermediate in SHR-F hearts. Levels of atrial natriuretic factor (ANF) mRNA were elevated threefold in the LV of SHR-NF (P<.05) but were not significantly increased in the RV of SHR-NF compared with WKY rats. During the transition to failure (SHR-F versus SHR-NF), ANF mRNA levels increased an additional 1.6-fold in the LV and were elevated 4.7-fold in the RV (both P<.05). Levels of sarcoplasmic reticulum Ca2+-ATPase (SRCA) mRNA were maintained in the LV of hypertensive and failing hearts at levels not significantly different from WKY values. In contrast, the level of RV SRCA mRNA was 24% less in SHR-NF compared with WKY rats, and during the transition to failure, this difference was not significantly exacerbated (29% less than the WKY value). The levels of fibronectin and pro-α1(I) and pro-α1(III) collagen mRNAs were not significantly elevated in either ventricle of the SHR-NF group but were fourfold to fivefold higher in both ventricles of SHR- F (all P<.05). The increase in fibronectin gene expression was at least partially explained by an elevation in the level of the EIIIA-containing isoform, an alternatively spliced variant expressed during wound healing and pressure overload hypertrophy. Transforming growth factor-β1 (TGF-β1) mRNA abundance was not elevated in ventricles of SHR-NF but increased 1.3- fold in the LV and twofold in the RV during the transition to heart failure compared with SHR-NF values (both P<.05). The decrease in α-myosin heavy chain mRNA levels in SHR-F hearts represents a pretranslational basis for the slowed contraction previously observed in cardiac muscle from these hearts. The survey of specific contractile protein mRNAs provides no evidence of a downregulation of these genes during the transition to heart failure. The increase in fibronectin and collagen mRNA levels suggests that the previously observed increase in interstitial fibrosis in cardiac muscles of failing hearts is regulated at the level of gene expression. The increase in abundance of TGF-β1 mRNA in conjunction with the upregulation of fibronectin and collagen genes suggests that activation of TGF-β1 gene expression may be a mechanism initiating interstitial fibrosis during the transition from stable hypertrophy to failure.

Original languageEnglish (US)
Pages (from-to)23-32
Number of pages10
JournalCirculation research
Volume75
Issue number1
DOIs
StatePublished - Jul 1994

Keywords

  • collagen
  • fibronectin
  • heart failure
  • myosin heavy chain
  • myosin light chain
  • sarcoplasmic reticulum Ca- ATPase
  • spontaneously hypertensive rats
  • transforming growth factor-β
  • α-actin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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