title: Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling.
abstract: Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Paffett
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: E Sage
authors.initials: ES
authors.lastname: Colombo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Selita N
authors.initials: SN
authors.lastname: Lucas
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Tamara
authors.initials: T
authors.lastname: Anderson
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Monique
authors.initials: M
authors.lastname: Nysus
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Norenberg
authors.affiliation: inviCRO, LLC., Boston, Massachusetts, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Gershman
authors.affiliation: inviCRO, LLC., Boston, Massachusetts, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hesterman
authors.affiliation: inviCRO, LLC., Boston, Massachusetts, United States of America.
authors.forename: Jack
authors.initials: J
authors.lastname: Hoppin
authors.affiliation: McAllister Heart Institute and Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Monte
authors.initials: M
authors.lastname: Willis
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015687:Cell Hypoxia; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology*; D006400:Hematocrit; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications; D051379:Mice; D009124:Muscle Proteins / Q000172:deficiency / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000503:physiopathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases