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Author
Alejandro Vega -
Discovery PI
Soban Umar, MD, PhD
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Project Co-Author
Varina Clark Onwunyi, MD, Somanshu Banerjee, PhD, Soyun Park, MD, Muhib Haidari, MD, Asif Razee, PhD, Soban Umar, MD, PhD
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Abstract Title
TRPV4 as a Potential Therapeutic Target for Pulmonary Hypertension-Induced Right Ventricular Failure
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Discovery AOC Petal or Dual Degree Program
Basic, Clinical, & Translational Research
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Abstract
Background: Right ventricular failure (RVF) is a common and fatal consequence of pulmonary hypertension (PH) and is a major determinant of morbidity and mortality. The transient receptor potential vanilloid type 4 (TRPV4) channel is a Ca2+ permeable, nonselective cation channel, and its role in PH-induced RVF (PH-RVF) is elusive. We hypothesize that TRPV4 activation mediates PH-RVF and TRPV4 inhibition may rescue PH-RVF by reducing RV hypertrophy, fibrosis and inflammation.
Methods: Male SD rats received s.c. Monocrotaline (MCT, 60mg/kg, n=9; 30-days), Sugen (20mg/kg, n=9; 3-wk hypoxia+2-wk normoxia; SuHx) or PBS (CTRL, n=9). Some MCT rats received TRPV4 agonist (GSK790A) or vehicle from day 0-30 while others received TRPV4 specific antagonist HC067047 or vehicle from day 14-30 (n=5). Echo, catheterization, RV-RNASeq, qPCR, WB, and IF validation were performed. RNASeq analysis was performed on human decompensated-RVF vs Control (GSE198618), and human RVs were assessed for fibrosis and inflammation. Human cardiac fibroblasts (HCFs) were treated with TRPV4 agonist (under normoxia) and antagonist (under hypoxia+TGFβ1).
Results: RNA-sequencing demonstrated an increase in hypertrophic, inflammatory, and fibrotic pathways and genes and an increase in TRPV4 expression in rat MCT, SuHx, PAB and human compensated and decompensated RVF compared to controls. RNA-sequencing also demonstrated increased downstream mediators of TRPV4 (collagens, ANP, BNP, inflammatory mediators) in rats and human RVF. Immunofluorescence imaging demonstrated increased colocalization of TRPV4 in RV cardiomyocytes, fibroblasts, and macrophages in PH-RVF. Interestingly, there was no significant increase in TRPV4 expression in the lungs of MCT and SuHx rats compared to controls. TRPV4 specific agonist GSK790A induced early PH-RVF in MCT rats in vivo and fibroblast to myofibroblast transition (FB-MFB) in vitro. Additionally, TRPV4 specific antagonist HC067047 rescued PH-RVF in MCT rats by improving RV function and reducing RV hypertrophy, fibrosis, and inflammation. Finally, TRPV4 specific antagonist GSK3874 inhibited FB-MFB transition in vitro and induced reversal of pro-fibrotic and inflammatory transcriptomic signature in HCF.
Conclusions: Pharmacological inhibition of TRPV4 rescues PH-RVF via reducing RV hypertrophy, fibrosis and inflammation and may serve as a novel therapeutic target.
Keywords: Right ventricular failure; Pulmonary hypertension; TRPV4 channel; Cardiac hypertrophy; Cardiac fibrosis; Inflammation; Monocrotaline rat model; Sugen/Hypoxia model; Pharmacological inhibition;