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

Abstract

HomeCirculationVol. 146, No. 5Response by Veith et al to Letter Regarding Article, “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Veith et al to Letter Regarding Article, “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension” Christine Veith, PhD, Hossein A. Ghofrani, MD and Norbert Weissmann, PhD Christine VeithChristine Veith https://orcid.org/0000-0002-5251-3364 Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University. Search for more papers by this author , Hossein A. GhofraniHossein A. Ghofrani https://orcid.org/0000-0002-2029-4419 Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University. Search for more papers by this author and Norbert WeissmannNorbert Weissmann https://orcid.org/0000-0003-2675-3871 Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University. Search for more papers by this author Originally published1 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060917Circulation. 2022;146:e16–e17In Response:We thank Jin et al for their positive comments on our recently published study showing that secreted protein acidic and rich in cysteine (SPARC) acts as a novel regulator of vascular cell function in pulmonary hypertension (PH). In detail, transcriptomic analysis identified Sparc as 1 gene consistently downregulated in the pulmonary vasculature of reoxygenated mice. SPARC was vice-versa upregulated in chronic hypoxia-induced PH in mice as well as in patients with idiopathic pulmonary arterial hypertension. Moreover, SPARC regulated vascular cell function. In vivo, Sparc knockdown by Sparc-specific short-hairpin RNA improved hemodynamic and cardiac function in PH mice.1As 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.2-4 Thus, on the basis of numerous precedents in this field, potential novel treatment targets derived from hypoxia-induced PH animal models deserve further exploration as potential PAH therapies. However, we agree with Jin and colleagues that such investigations can and should be complemented by other animal models (eg, SU5416+hypoxia, monocrotaline application in rats) as suggested.As stated by Jin et al, SPARC and SPARCL1 (dys-)regulation has previously been observed in right heart hypertrophy, indicating that SPARC family members might play a potential role in right ventricular homeostasis. As also acknowledged by the authors, our study focused solely on the pulmonary vasculature. Our transcriptomic approach exclusively identified the SPARC family member Sparc as 1 of the genes consistently downregulated in all reoxygenation time points investigated. The regulation of other SPARC family members, including Sparcl1, was less consistent. In this regard, differential gene expression of Sparc and Sparcl1 was already observed in a previous study.5 Nevertheless, we of course agree that further investigation of SPARC and its family members in cardiac remodeling and function in both experimental and human PH will further enhance our knowledge about their role as a modulator, driver, or possible therapeutic target of PH.We have to disagree, however, with Jin et al about their statement that Sparc silencing did not protect against PH. In our study, we convincingly show that Sparc silencing by Sparc-specific short-hairpin RNA improved hemodynamic and cardiac function in PH mice.1 Their interpretation that excessive downregulation of SPARC might aggravate pulmonary arterial smooth muscle proliferation and PH is entirely based on our findings in congenital knockout mouse experiments. Our best explanation so far, as also explained in our article, is that SPARC plays an essential role during development—if knocked out, this is compensated for by counter-regulatory mechanisms, potentially promoting pulmonary vascular disease. It is clear that this aspect warrants further investigation. For instance, conditional as well as cell type–specific knockout strategies in hypoxia-induced PH development in mice could be used to further unravel the role of SPARC.Article InformationSources of FundingThis work was funded by the German Research Foundation (Project 268555672-SFB 1213, Project A06, B08).Disclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circ