SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension

Abstract

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.

Prognostic significance of SPARC expression in non‑small cell lung cancer: A meta‑analysis and bioinformatics analysis

“…In addition, the population selected in the dataset for clinical pathological data statistics and survival prognosis analysis may exhibit regional or genetic differences and certain differences in human physique and living environment are likely to be present. Increases in the serum levels of SPARC may occur as part of biological functions and processes such as tumors and obesity; of note, SPARC expression levels were upregulated in the lung during hypoxia induction in a mouse model, and the hypoxia-inducible factor 2A signaling pathway induces SPARC expression, which in turn has an effect on proliferation and apoptosis of tumor cells in humans (59)(60)(61). It has also been indicated that the SPARC signaling pathway induces albumin-bound paclitaxel, which enhances initial chemoresistance of patients with lung cancer and this may also be used to optimize individual gene therapy regimens, which are important for mechanistic studies, animal models and clinical treatment evaluation in NSCLC (62).…”

Response by Veith et al to Letter Regarding Article, “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension”

“…In vivo, Sparc knockdown by Sparc-specific short-hairpin RNA improved hemodynamic and cardiac function in PH mice. 1 As stated by Jin et al, the pathophysiology between World Health Organization group 1 PH (PAH) and group 3 PH (PH caused by hypoxia and/or lung diseases) differs. Nevertheless, previous studies have shown that pharmacological approaches that are meanwhile approved for the treatment of patients with PAH prevented or alleviated PH in hypoxic animal models.…”

“…In vivo, Sparc knockdown by Sparc -specific short-hairpin RNA improved hemodynamic and cardiac function in PH mice. 1…”

Letter by Jin et al Regarding Article, “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension”

“…the present study focused mainly on pulmonary vasculature and neglected secondary right-sided heart failure. 1 To the best of our knowledge, the exact role of SPARC has never been addressed in pathological right ventricular remodeling. SPARC has recently been reported to regulate E-cadherin protein expression and to be involved in endothelial to mesenchymal transition, 4 an essential process implicated in PH development and progression.…”