Iloprost reverses established fibrosis in experimental right ventricular failure

Abstract

Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV).Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 μg·kg −1 nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre-and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy.Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-β1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-β1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation.Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover. @ERSpublications Prostanoids have load-independent effects on the right ventricle that could contribute to improvement in #PAH http://ow.ly/Ae5Om

17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension

“…Second, while we demonstrate favorable effects of endogenous or exogenous E 2 on proapoptotic signaling, eNOS phosphorylation, and autophagic flux, these parameters were not significantly affected by SuHx or sex. While this may suggest that these pathways do not play a role in RV failure, this is unlikely in light of previously published data that demonstrate pathophysiological relevance (6,14,29,46,47,52). A more likely explanation is that the present studies were underpowered to detect more profound changes in these endpoints.…”

“…Since our correlation analyses linked impaired autophagic flux to worsening RV function and remodeling, these data suggest that improved autophagic flux may, at least in part, be a mechanism of how E 2 mediates RV-protective effects after acute exercise. Along these lines, stimulatory effects on autophagy have recently been suggested as a mediator of RV-protective and anti-fibrotic effects of the prostacyclin ilopprost (14). Taken together, these data suggest that autophagy may be a potentially important modifier of RV function in PAH.…”

Myocardial inflammation in experimental acute right ventricular failure: Effects of prostacyclin therapy

“…44 Prostacyclin is able to reduce TNF-α-induced expression of VCAM1 in endothelial cells, 45 which is in accordance with the present results showing decreased VCAM1 expression after the epoprostenol infusion. Moreover, a recent study showed that prostacyclin is able to reverse established RV fibrosis in an experimental model of RV failure by preventing collagen synthesis and by increasing collagen turnover, 46 which is probably linked to the effects of prostacyclin on inflammatory processes. However, because of the different timing of myocardial sampling and the difficulty of performing biopsies in such an acute experimental model, we cannot exclude (at least partly) some timing effects on the activation of inflammatory processes, even if RV failure on acute transient increased afterload has been shown to be persist at least 120 minutes after the restoration of loading conditions.…”

Autophagy mediates oral submucous fibrosis

“…Indeed, pathologically activated autophagy has been associated with various fibrotic diseases (23)(24)(25)(26)(27)). An overexpression of the autophagy marker LC3 was observed in human samples from a number of patients with OSF.…”