Open AccessLimiting collagen turnover via collagenase‐resistance attenuates right ventricular dysfunction and fibrosis in pulmonary arterial hypertension
Author(s) -
Golob Mark J.,
Wang Zhijie,
Prostrollo Anthony J.,
Hacker Timothy A.,
Chesler Naomi C.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12815
Subject(s) - pulmonary hypertension , pressure overload , medicine , cardiology , pulmonary artery , afterload , fibrosis , ventricular remodeling , muscle hypertrophy , right ventricular hypertrophy , heart failure , vascular resistance , ventricular pressure , blood pressure , cardiac hypertrophy
Pulmonary arterial hypertension ( PAH ) is a severe form of pulmonary hypertension in which right ventricular ( RV ) afterload is increased and death typically occurs due to decompensated RV hypertrophy and failure. Collagen accumulation has been implicated in pulmonary artery remodeling, but how it affects RV performance remains unclear. Here, we sought to identify the role of collagen turnover, defined as the balance between collagen synthesis and degradation, in RV structure and function in PAH . To do so, we exposed mutant (Col1a1 R/R ) mice, in which collagen type I degradation is impaired such that collagen turnover is reduced, and wild‐type (Col1a1 +/+ ) littermates to 14 days of chronic hypoxia combined with SUGEN treatment (HySu) to recapitulate characteristics of clinical PAH . RV structure and function were measured by echocardiography, RV catheterization, and histology. Despite comparable increases in RV systolic pressure (Col1a1 +/+ : 46 ± 2 mmHg; Col1a1 R/R : 47 ± 3 mmHg), the impaired collagen degradation in Col1a1 R/R mice resulted in no RV collagen accumulation, limited RV hypertrophy, and maintained right ventricular‐pulmonary vascular coupling with HySu exposure. The preservation of cardiac function in the mutant mice indicates a beneficial role of limited collagen turnover via impaired degradation in RV remodeling in response to chronic pressure overload. Our results suggest novel treatments that reduce collagen turnover may offer a new therapeutic strategy for PAH patients.