Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension

Lian Tian, Monica Neuber-Hess, Jeffrey Mewburn, Asish Dasgupta, Kimberly Dunham-Snary, Danchen Wu, Kuang Hueih Chen, Zhigang Hong, Willard W. Sharp, Shelby Kutty, Stephen L. Archer

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Abstract: Right ventricular (RV) function determines prognosis in pulmonary arterial hypertension (PAH). We hypothesize that ischemia causes RV dysfunction in PAH by triggering dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. RV function was compared in control rats (n = 50) versus rats with monocrotaline-induced PAH (MCT-PAH; n = 60) both in vivo (echocardiography) and ex vivo (RV Langendorff). Mitochondrial membrane potential and morphology and RV function were assessed before or after 2 cycles of ischemia-reperfusion injury challenge (RV-IR). The effects of Mdivi-1 (25 μM), a Drp1 GTPase inhibitor, and P110 (1 μM), a peptide inhibitor of Drp1-Fis1 interaction, were studied. We found that MCT caused RV hypertrophy, RV vascular rarefaction, and RV dysfunction. Prior to IR, the mitochondria in MCT-PAH RV were depolarized and swollen with increased Drp1 content and reduced aconitase activity. RV-IR increased RV end diastolic pressure (RVEDP) and mitochondrial Drp1 expression in both control and MCT-PAH RVs. IR depolarized mitochondria in control RV but did not exacerbate the basally depolarized MCT-PAH RV mitochondria. During RV IR mdivi-1 and P110 reduced Drp1 translocation to mitochondria, improved mitochondrial structure and function, and reduced RVEDP. In conclusion, RV ischemia occurs in PAH and causes Drp1-Fis1-mediated fission leading to diastolic dysfunction. Inhibition of mitochondrial fission preserves RV function in RV-IR. Key messages: Right ventricular ischemia reperfusion (RV-IR) causes RV diastolic dysfunction.IR-induced mitochondrial fission causes RV diastolic dysfunction.In RV-IR Drp1 translocates to mitochondria, binds Fis1 and causes fission and injury.A baseline RV mitochondriopathy in MCT PAH resembles IR-induced mitochondrial injury.Drp1 inhibitors (Mdivi-1 and P110) preserve RV diastolic function post RV-IR.

Original languageEnglish (US)
Pages (from-to)381-393
Number of pages13
JournalJournal of Molecular Medicine
Volume95
Issue number4
DOIs
StatePublished - Apr 1 2017

Keywords

  • Diastolic dysfunction
  • Ischemia-reperfusion injury
  • Mdivi-1
  • Mitochondrial division inhibitor 1
  • Mitochondrial membrane potential
  • Pulmonary arterial hypertension

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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