Abstract
Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here, we show that miR‐322‐5p (the rodent orthologue of miR‐424‐5p) expression is decreased in the right ventricle of monocrotaline‐treated rats, a model of PAH, whereas a putative target insulin‐like growth factor 1 (IGF‐1) is increased. IGF‐1 mRNA was enriched 16‐fold in RNA immunoprecipitated with Ago2, indicating binding to miR‐322‐5p. In cell transfection experiments, miR‐322‐5p suppressed the activity of a luciferase reporter containing a section of the IGF‐1 3′ untranslated region (UTR) as well as IGF‐1 mRNA and protein levels. Taken together, these data suggest that miR‐322 targets IGF‐1, a process downregulated in PAH‐related RV hypertrophy.
Highlights
Pulmonary arterial hypertension (PAH) is a pathophysiological process characterised by high, precapillary pulmonary vascular resistance [1]
Contribute to the maintenance of cell size [10,11]. When these are in balance, cell size is maintained; the right ventricle (RV) cardiomyocyte hypertrophy observed in PAH requires the rate of protein synthesis to exceed that of protein breakdown
insulin-like growth factor 1 (IGF-1) expression was significantly increased in the RVs of MCT rats compared to phosphate-buffered saline (PBS) controls (3.5fold, P = 0.0028), suggesting an upregulation of IGF-1 signalling promoting growth (Fig. 1D)
Summary
Pulmonary arterial hypertension (PAH) is a pathophysiological process characterised by high, precapillary pulmonary vascular resistance [1]. Prognosis for patients varies, with average survival rates of 58–67% 3 years after diagnosis for idiopathic PAH [5,6], with cause of death normally being attributed to right ventricular failure [7]. One widely used model of PAH is monocrotaline (MCT) treatment of rats [8] In this model, following a single dose of MCT the animals develop elevated pulmonary vascular resistance leading to right heart hypertrophy within 4 weeks [9]. MiR-322-5p targets IGF-1 and is reduced in PAH contribute to the maintenance of cell size [10,11] When these are in balance, cell size is maintained; the RV cardiomyocyte hypertrophy observed in PAH requires the rate of protein synthesis to exceed that of protein breakdown
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