title: Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension.
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.
  
  
  
  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.
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Lian
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Neuber-Hess
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Mewburn
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Asish
authors.initials: A
authors.lastname: Dasgupta
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Dunham-Snary
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Danchen
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Kuang-Hueih
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Willard W
authors.initials: WW
authors.lastname: Sharp
authors.affiliation: Department of Pediatric Cardiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Shelby
authors.initials: S
authors.lastname: Kutty
authors.affiliation: Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada. stephen.archer@queensu.ca.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D034281:Dynamins / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D018497:Ventricular Dysfunction, Right / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: C503403:Fis1 protein, rat; D024101:Mitochondrial Proteins; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: Diastolic dysfunction; Ischemia-reperfusion injury; Mdivi-1; Mitochondrial division inhibitor 1; Mitochondrial membrane potential; Pulmonary arterial hypertension