Lung remodeling and pulmonary hypertension after myocardial infarction: Pathogenic role of reduced caveolin expression

Jean François Jasmin, Isabelle Mercier, Robert Hnasko, Michelle W C Cheung, Herbert B. Tanowitz, Jocelyn Dupuis, Michael P. Lisanti

Research output: Contribution to journalArticle

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Abstract

Objectives: Pulmonary hypertension (PH) and lung structural remodeling are frequent complications of congestive heart failure (CHF). Yet, the molecular mechanisms involved in CHF-induced PH and lung remodeling remain unknown. Caveolins (Cav-1, -2 and -3) are the principal structural proteins of the vesicular invaginations of the plasma membrane, termed caveolae. Mice with homozygous deletion of the caveolin-1 gene (Cav-1(-/-)) have been shown to develop dilated cardiomyopathy, PH and lung structural remodeling, characterized by hypercellularity and thickening of the alveolar septa. However, the physiological relevance of these observations for the pathogenesis of PH and lung remodeling remains to be determined. Methods and results: Here, we investigate the natural behavior of the endogenous caveolin proteins during the development of PH and lung structural remodeling, using a rat model of myocardial infarction (MI). MI was induced in male Wistar rats by ligating the left anterior coronary artery. Two weeks post-MI, rats were anesthetized and hemodynamic and morphometric measurements were obtained. Rats subjected to MI developed marked PH, lung structural remodeling and right ventricular hypertrophy (RVH). Both immunoblot analysis and immunohistochemistry dramatically show that Cav-1 and Cav-2 expression is downregulated to almost undetectable levels in the lungs of post-MI rats. Mechanistically, the reduced expression of caveolins was associated with the increased tyrosine- phosphorylation of the signal transducer and activator of transcription-3 (STAT3) and the upregulation of cyclin D1 and D3 expression. We also show that STAT3 is hyperphosphorylated, and cyclin D1 and D3 levels are dramatically upregulated, in lung tissue samples derived from Cav-1 (-/-)- and Cav-2 (-/-)-deficient mice. Conclusions: Thus, down-modulation of pulmonary Cav-1 and Cav-2 expression in rats subjected to MI may represent an initiating mechanism leading to the activation of the STAT3/Cyclins pathway and, ultimately, to the development of PH and lung structural remodeling.

Original languageEnglish (US)
Pages (from-to)747-755
Number of pages9
JournalCardiovascular Research
Volume63
Issue number4
DOIs
StatePublished - Sep 1 2004

Fingerprint

Caveolins
Pulmonary Hypertension
Myocardial Infarction
Lung
STAT3 Transcription Factor
Cyclin D3
Caveolin 1
Cyclin D1
Heart Failure
Right Ventricular Hypertrophy
Caveolae
Cyclins
Dilated Cardiomyopathy
Tyrosine
Wistar Rats
Coronary Vessels
Up-Regulation
Down-Regulation
Hemodynamics
Immunohistochemistry

Keywords

  • Caveolin proteins
  • Cyclins
  • Lung remodeling
  • Myocardial infarction
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Jasmin, J. F., Mercier, I., Hnasko, R., Cheung, M. W. C., Tanowitz, H. B., Dupuis, J., & Lisanti, M. P. (2004). Lung remodeling and pulmonary hypertension after myocardial infarction: Pathogenic role of reduced caveolin expression. Cardiovascular Research, 63(4), 747-755. https://doi.org/10.1016/j.cardiores.2004.05.018

Lung remodeling and pulmonary hypertension after myocardial infarction : Pathogenic role of reduced caveolin expression. / Jasmin, Jean François; Mercier, Isabelle; Hnasko, Robert; Cheung, Michelle W C; Tanowitz, Herbert B.; Dupuis, Jocelyn; Lisanti, Michael P.

In: Cardiovascular Research, Vol. 63, No. 4, 01.09.2004, p. 747-755.

Research output: Contribution to journalArticle

Jasmin, JF, Mercier, I, Hnasko, R, Cheung, MWC, Tanowitz, HB, Dupuis, J & Lisanti, MP 2004, 'Lung remodeling and pulmonary hypertension after myocardial infarction: Pathogenic role of reduced caveolin expression', Cardiovascular Research, vol. 63, no. 4, pp. 747-755. https://doi.org/10.1016/j.cardiores.2004.05.018
Jasmin, Jean François ; Mercier, Isabelle ; Hnasko, Robert ; Cheung, Michelle W C ; Tanowitz, Herbert B. ; Dupuis, Jocelyn ; Lisanti, Michael P. / Lung remodeling and pulmonary hypertension after myocardial infarction : Pathogenic role of reduced caveolin expression. In: Cardiovascular Research. 2004 ; Vol. 63, No. 4. pp. 747-755.
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