ProT-α gene transfer attenuates cardiopulmonary remedying and mortality in a flow-induced pulmonary hypertension rat model

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Abstract

BACKGROUND: ProT is a cell survival gene, which modulates oxidative stress and transforming growth factor (TGF)-β signaling. We hypothesized that the delivery of the ProT cDNA gene in rats could protect against right heart dysfunction secondary to pulmonary hypertension (PH) induced by left-to-right shunt. METHODS: A 2-hit rat model of flow-induced PH was used, and a single intravenous injection of adenoviral vectors (2 billion plaque-forming unit) carrying ProT or Luc gene was administered. The animals were euthanized 21 days after gene delivery to assess cardiopulmonary function, serum biochemistry, pulmonary artery (PA), and vasomotor reactivity. Immunohistology and immunoblotting of PA tissues were also performed. RESULTS: ProT transduction significantly reduced PA pressure, right ventricle muscle mass, and wall stress, thereby improving the overall survival of the treated rat. Increased production of ProT through gene therapy preserved both the smooth muscle myosin heavy chain-II and α-smooth muscle actin while counteracting the abundance of TGF-β in PA. Protein abundances of phosphorylated p47-phox, heme oxygenase-1, caspase-3, inducible nitric oxide synthase, cyclo-oxygenase 2, and monocyte chemoattractant protein-1 in PA tissues were reduced. ProT also preserved microRNA-223, thereby suppressing the abundance of PARP-1, which is independent of hypoxia-inducible factor-1α signaling. CONCLUSIONS: ProT gene transduction improved PA function by reducing oxidative stress, attenuating inflammation, and preserving the contractile phenotype of vascular smooth muscle cells. The modification of microRNA-223–associated downstream signaling through ProT transduction may play an important role in mitigating cardiopulmonary remodeling in flow-induced PH.

Original languageEnglish
Pages (from-to)1126-1135
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume39
Issue number10
DOIs
Publication statusPublished - 2020 Oct

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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