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. 2013 Jul 30;8(7):e70802.
doi: 10.1371/journal.pone.0070802. Print 2013.

Biventricular remodeling in murine models of right ventricular pressure overload

Navin K Kapur  1 , Vikram Paruchuri, Mark J Aronovitz, Xiaoying Qiao, Emily E Mackey, Gerard H Daly, Kishan Ughreja, Jonathan Levine, Robert Blanton, Nicholas S Hill, Richard H Karas
Affiliations

Biventricular remodeling in murine models of right ventricular pressure overload

Navin K Kapur et al. PLoS One. .

Abstract

Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGFβ1).

Methods: Adult, male mice underwent constriction of the pulmonary artery or thoracic aorta as models of primary and secondary RVPO, respectively. Conductance catheterization was performed followed by tissue analysis for changes in myocyte hypertrophy and fibrosis.

Results: Both primary and secondary RVPO decreased biventricular stroke work however RV instantaneous peak pressure (dP/dtmax) and end-systolic elastance (Ees) were preserved in both groups compared to controls. In contrast, left ventricular (LV) dP/dtmax and LV-Ees were unchanged by primary, but reduced in the secondary RVPO group. The ratio of RV:LV ventriculo-arterial coupling was increased in primary and reduced in secondary RVPO. Primary and secondary RVPO increased RV mass, while LV mass decreased in primary and increased in the secondary RVPO groups. RV fibrosis and hypertrophy were increased in both groups, while LV fibrosis and hypertrophy were increased in secondary RVPO only. RV calcineurin expression was increased in both groups, while LV expression increased in secondary RVPO only. Biventricular TGFβ1 expression was increased in both groups.

Conclusion: These data identify distinct effects of primary and secondary RVPO on biventricular structure, function, and expression of key remodeling pathways.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Biventricular conductance catheterization in a closed-chest, non-invasively ventilated mouse.
A) Hemodynamic tracings illustrating pressure volume (PV) catheters tracking from the right atrium (RA) to right ventricle (RV) via the right external jugular vein and aorta (Ao) to left ventricle (LV) via the right carotid artery via a suprasternal incision in a closed-chest mouse (*, salivary gland). B) Representative steady-state PV loops in mouse models of (i) primary and (ii) secondary right ventricular pressure overload (RVPO) (blue loops represent sham operated animals).
Figure 2
Figure 2. Biventricular hemodynamics in models of primary and secondary right ventricular pressure overload (RVPO).
A) Peak systolic pressure, B) End-diastolic pressure, C) Heart rate, D) End-diastolic volume, E) End-systolic volume, F) Stroke volume, G) dP/dt max, H) Ventricular stroke work, and I) Cardiac output. *, p
Figure 3
Figure 3. Hypertrophic remodeling in models of primary and secondary right ventricular pressure overload (RVPO).
A) Representative histologic staining of right (RV) and left (LV) ventricular tissue and B) bar graph of RV and LV cardiomyocyte cross-sectional areas after primary and secondary RVPO. C) Western blot and D) bar graph of RV and LV calcineurin protein expression normalized to GAPDH. E) Calcineurin-Aβ (CN-PP), F) brain natriuretic peptide (BNP), G) beta-myosin heavy chain (b-MHC), and H) sarcoplasmic reticulum Ca2+ATPase (SERCa) gene expression normalized to total ribosomal RNA (rRNA). *, p<0.05 vs Sham for the corresponding ventricle; †, p<0.05 vs Primary RVPO for the corresponding ventricle; ‡, p<0.05 vs the RV for the same RVPO condition.
Figure 4
Figure 4. Fibrotic remodeling in models of primary and secondary right ventricular pressure overload (RVPO).
A) Picrosirius red staining for collagen abundance and B) quantitation of percent fibrosis in the right (RV) and left ventricle (LV) after primary and secondary RVPO. C) Western blot and D) bar graph of Type I collagen normalized to GAPDH. E–F) Gene expression of transforming growth factor beta 1 (TGFβ1) and endoglin normalized to ribosomal RNA (rRNA). G–H) Quantified protein expression of phosphorylated ERK (pERK) normalized to total ERK and phosphorylated Smad-3 normalized to total Smad-3. *, p
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