Aims The cytoskeletal signaling protein four and-a-half LIM domains 1 (FHL-1) has recently been identified as a novel key player in pulmonary hypertension as well as in left heart diseases. In this regard, FHL-1 has been implicated in dysregulated hypertrophic signaling in pulmonary arterial smooth muscle cells leading to pulmonary hypertension. In mice, FHL-1-deficiency (FHL-1 −/− ) led to an attenuated hypertrophic signaling associated with a blunted hypertrophic response of the pressure-overloaded left ventricle (LV). However, the role of FHL-1 in right heart hypertrophy has not yet been addressed. Methods and resultsWe investigated FHL-1 expression in C57Bl/6 mice subjected to chronic biomechanical stress and found it to be enhanced in the right ventricle (RV). Next, we subjected FHL-1 −/− and corresponding wild-type mice to pressure overload of the RV by pulmonary arterial banding for various time points. However, in contrast to the previously published study in LV-pressure overload, which was confirmed here, RV hypertrophy and hypertrophic signaling was not diminished in FHL-1 −/− mice. In detail, right ventricular pressure overload led to hypertrophy, dilatation and fibrosis of the RV from both FHL-1 −/− and wild-type mice. RV remodeling was associated with impaired RV function as evidenced by reduced tricuspid annular plane systolic excursion. Additionally, PAB induced upregulation of natriuretic peptides and slight downregulation of phospholamban and ryanodine receptor 2 in the RV. However, there was no difference between genotypes in the degree of expression change. Conclusion FHL-1 pathway is not involved in the control of adverse remodeling in the pressure overloaded RV.
Background: Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMC) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVEC). Upon re-exposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, we aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature. Methods: Following a microarray analysis, we assessed the role of secreted protein acidic and rich in cysteine (SPARC) in PH using lung tissue from idiopathic pulmonary arterial hypertension (IPAH) patients as well as from chronic hypoxic mice. In vitro studies were conducted in primary human PASMC and PMVEC. In vivo function of SPARC was proven in chronic hypoxia-induced PH in mice by using an AAV-mediated Sparc knockdown approach. Results: C57BL/6J mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia for different time points. Microarray analysis of the pulmonary vascular compartment after laser microdissection identified Sparc as one of the genes down-regulated at all re-oxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in IPAH, although SPARC plasma levels were not elevated in PH. Transforming growth factor (TGF)-β1 or hypoxia-inducible factor (HIF)-2A signaling pathways induced SPARC expression in human PASMC. In loss of function studies, SPARC silencing enhanced apoptosis and reduced proliferation. In gain of function studies, elevated SPARC levels induced PASMC but not PMVEC proliferation. Co-culture and conditioned medium experiments revealed that PMVEC-secreted SPARC acts as a paracrine factor triggering PASMC proliferation. Against our expectations, in vivo congenital Sparc knockout mice were not protected from hypoxia-induced PH, most probably due to counter-regulatory pro-proliferative signaling. However, AAV-mediated Sparc knockdown in adult mice significantly improved hemodynamic and cardiac function in PH mice. Conclusions: Our study provided evidence for the involvement of SPARC in the pathogenesis of human PH and chronic hypoxia-induced PH in mice, most probably by affecting vascular cell function.
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