{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T03:56:55Z","timestamp":1777089415476,"version":"3.51.4"},"posted":{"date-parts":[[2024,5,3]]},"group-title":"Physiology","reference-count":53,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pulmonary hypertension (PH)-induced right ventricular (RV) failure (PH-RVF) is a significant prognostic determinant of mortality and is characterized by RV hypertrophy, endothelial-to-mesenchymal transition (EndMT), fibroblast-to-myofibroblast transition (FMT), fibrosis, and extracellular matrix (ECM)-remodeling. Despite the importance of RV function in PH, the mechanistic details of PH-RVF, especially the regulatory control of RV EndMT, FMT, and fibrosis, remain unclear. The action of transcription factor Snai1 is shown to be mediated through LOXL2 recruitment, and their co-translocation to the nucleus, during EndMT progression. We hypothesize that RV EndMT and fibrosis in PH-RVF are governed by the TGF\u03b21-Snai1-LOXL2 axis. Furthermore, targeting Snai1 could serve as a novel therapeutic strategy for PH-RVF.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Adult male Sprague Dawley rats (250-300g) received either a single subcutaneous injection of Monocrotaline (MCT, 60mg\/kg, n=9; followed for 30-days) or Sugen (SU5416 20mg\/kg, n=9; 10% O\n                    <jats:sub>2<\/jats:sub>\n                    hypoxia for 3-weeks followed by normoxia for 2-weeks) or PBS (CTRL, n=9). We performed secondary bioinformatics analysis on the RV bulk RNA-Seq data from MCT, SuHx, and PAB rats and human PH-PVF. We validated EndMT and FMT and their association with Snai1 and LOXL2 in the RVs of MCT and SuHx rat models and human PH-RVF using immunofluorescence, qPCR, and Western blots. For\n                    <jats:italic>in vivo<\/jats:italic>\n                    Snai1 knockdown (Snai1-KD), MCT-rats either received Snai1-siRNA (n=7; 5nM\/injection every 3-4 days; 4-injections) or scramble (SCRM-KD; n=7) through tail vein from day 14-30 after MCT. Echocardiography and catheterization were performed terminally. Bulk RNASeq and differential expression analysis were performed on Snai1- and SCRM-KD rat RVs.\n                    <jats:italic>In vitro<\/jats:italic>\n                    Snai1-KD was performed on human coronary artery endothelial cells (HCAECs) and human cardiac fibroblasts (HCFs) under hypoxia+TGF\u03b21 for 72-hrs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    PH-RVF had increased RVSP and Fulton index and decreased RV fractional area change (RVFAC %). RV RNASeq demonstrated EndMT as the common top-upregulated pathway between rat (MCT, SuHx, and PAB) and human PH-RVF. Immunofluorescence using EndMT- and FMT-specific markers demonstrated increased EndMT and FMT in RV of MCT and SuHx rats and PH-RVF patients. Further, RV expression of TGF\u03b21, Snai1, and LOXL2 was increased in MCT and SuHx. Nuclear co-localization and increased immunoreactivity, transcript, and protein levels of Snai1 and LOXL2 were observed in MCT and SuHx rats and human RVs. MCT rats treated with Snai1-siRNA demonstrated decreased Snai1 expression, RVSP, Fulton index, and increased RVFAC. Snai1-KD resulted in decreased RV-EndMT, FMT, and fibrosis\n                    <jats:italic>via<\/jats:italic>\n                    a LOXL2-dependent manner. Further, Snai1-KD inhibited hypoxia+TGF\u03b21-induced EndMT in HCAECs and FMT in HCFs\n                    <jats:italic>in vitro<\/jats:italic>\n                    by decreasing perinuclear\/nuclear Snai1+LOXL2 expression and co-localization.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    RV-specific targeting of Snai1 rescues PH-RVF by inhibiting EndMT and Fibrosis\n                    <jats:italic>via<\/jats:italic>\n                    a LOXL2-mediated mechanism.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.04.30.591766","type":"posted-content","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T15:05:18Z","timestamp":1714748718000},"source":"Crossref","is-referenced-by-count":3,"title":["RV-specific Targeting of Snai1 Rescues Pulmonary Hypertension-induced Right Ventricular Failure by Inhibiting EndMT and Fibrosis\n                  <i>via<\/i>\n                  LOXL2 Mediated Mechanism"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8043-2457","authenticated-orcid":false,"given":"Somanshu","family":"Banerjee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varina R. 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