Analysis of the microRNA signature driving adaptive right ventricular hypertrophy in an ovine model of congenital heart disease

Rebecca Johnson Kameny, Youping He, Terry Zhu, Wenhui Gong, Gary W Raff, Cheryl J. Chapin, Sanjeev A. Datar, Jason T. Boehme, Akiko Hata, Jeffrey R. Fineman

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs (n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.

Original languageEnglish (US)
Pages (from-to)H847-H854
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume315
Issue number4
DOIs
StatePublished - Oct 1 2018

Fingerprint

Right Ventricular Hypertrophy
MicroRNAs
Heart Diseases
Sheep
Pulmonary Hypertension
Hypertrophy
NFATC Transcription Factors
Right Ventricular Function
Premature Mortality
Calcineurin
Dilatation
Fibrosis
Collagen
Down-Regulation

Keywords

  • Congenital heart disease
  • microRNA
  • Pulmonary hypertension
  • Right ventricular hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Analysis of the microRNA signature driving adaptive right ventricular hypertrophy in an ovine model of congenital heart disease. / Kameny, Rebecca Johnson; He, Youping; Zhu, Terry; Gong, Wenhui; Raff, Gary W; Chapin, Cheryl J.; Datar, Sanjeev A.; Boehme, Jason T.; Hata, Akiko; Fineman, Jeffrey R.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 315, No. 4, 01.10.2018, p. H847-H854.

Research output: Contribution to journalArticle

Kameny, Rebecca Johnson ; He, Youping ; Zhu, Terry ; Gong, Wenhui ; Raff, Gary W ; Chapin, Cheryl J. ; Datar, Sanjeev A. ; Boehme, Jason T. ; Hata, Akiko ; Fineman, Jeffrey R. / Analysis of the microRNA signature driving adaptive right ventricular hypertrophy in an ovine model of congenital heart disease. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 315, No. 4. pp. H847-H854.
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AU - Zhu, Terry

AU - Gong, Wenhui

AU - Raff, Gary W

AU - Chapin, Cheryl J.

AU - Datar, Sanjeev A.

AU - Boehme, Jason T.

AU - Hata, Akiko

AU - Fineman, Jeffrey R.

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N2 - The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs (n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.

AB - The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs (n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.

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