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ABSTRACT
Background
Caveolin-1 (cav-1) plays a role in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH is characterized by a loss of cav-1 in pulmonary arteries; however, less is known regarding its role in the hypertrophied right ventricle (RV). We aimed to characterize the role of cav-1 and Hsp90 in the RV of MCT-induced PAH and their impact on endothelial nitric oxide synthase (eNOS). Additionally, we focused on restoration of cav-1 expression with pioglitazone administration.
Methods
Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). Selected proteins (cav-1, eNOS, pSer1177eNOS, Hsp90) and mRNAs (cav-1α, cav-1β, eNOS) were determined in the RV and left ventricle (LV) 4 weeks later. In a separate MCT-induced PAH study, pioglitazone (10 mg/kg/d, orally) administration started on day 14 after MCT.
Results
MCT induced RV hypertrophy and lung enlargement. Cav-1 and pTyr14cav-1 were decreased in RV. Caveolin-1α (cav-1α) and caveolin-1β (cav-1β) mRNAs were decreased in both ventricles. Hsp90 protein was increased in RV. eNOS and pSer1177eNOS proteins were unchanged in the ventricles. eNOS mRNA was reduced in RV. Pioglitazone treatment increased oxygen saturation and pTyr14cav-1 vs. MCT group.
Conclusions
Restoration of pTyr14cav-1 did not lead to amelioration of the disease, nor did it prevent RV hypertrophy and fibrosis, which was indicated by an increase in Acta2, Nppb, Col3a1, and Tgfβ1 mRNA.
Acknowledgements
The work was supported by the following grants: APVV-15-0685 from the Slovak Research and Development Agency (Jan Klimas), APVV-19-0458 from the Slovak Research and Development Agency (Peter Krenek), and 1/0203/19 from the Science Grant Agency (VEGA), Slovak Republic (Peter Krenek).
Author contributionsAll authors contributed equally to this work.
Conflicts of interest None.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
Acta2, alpha smooth muscle actin; BW, body weight; cav-1, caveolin-1; cav-1α, caveolin-1 alpha; caveolin-1β, caveolin-1 beta; Col3a1, collagen type III alpha 1 chain; CON, control; ECL, enhanced chemiluminescence; eNOS, endothelial nitric oxide synthase; Hsp90, heat shock protein 90; LV, left ventricle; LVW, left ventricular weight; MCT, monocrotaline; NO, nitric oxide; Nppb, brain natriuretic peptide; PAH, pulmonary arterial hypertension; PIO, pioglitazone; PPARγ, peroxisome proliferator–activated receptor γ; pSer1177eNOS, eNOS phosphorylated on serine 1177; pTyr14cav-1, caveolin-1 phoshorylated on tyrosine 14; RV, right ventricle; RVW, right ventricular weight; SuHx, Sugen/hypoxia, Tgfβ1, transforming growth factor-β1.