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 journalArticle

17 Citations (Scopus)

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

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Mitochondrial Dynamics
Right Ventricular Dysfunction
Dynamins
Pulmonary Hypertension
Ischemia
Right Ventricular Function
Mitochondria
Proteins
Monocrotaline
Aconitate Hydratase
Blood Pressure
Right Ventricular Hypertrophy
Mitochondrial Membrane Potential
GTP Phosphohydrolases
Wounds and Injuries
Protein Transport
Reperfusion Injury
Reperfusion
Blood Vessels
Echocardiography

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)

Cite this

Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. / Tian, Lian; Neuber-Hess, Monica; Mewburn, Jeffrey; Dasgupta, Asish; Dunham-Snary, Kimberly; Wu, Danchen; Chen, Kuang Hueih; Hong, Zhigang; Sharp, Willard W.; Kutty, Shelby; Archer, Stephen L.

In: Journal of Molecular Medicine, Vol. 95, No. 4, 01.04.2017, p. 381-393.

Research output: Contribution to journalArticle

Tian, L, Neuber-Hess, M, Mewburn, J, Dasgupta, A, Dunham-Snary, K, Wu, D, Chen, KH, Hong, Z, Sharp, WW, Kutty, S & Archer, SL 2017, 'Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension', Journal of Molecular Medicine, vol. 95, no. 4, pp. 381-393. https://doi.org/10.1007/s00109-017-1522-8
Tian, Lian ; Neuber-Hess, Monica ; Mewburn, Jeffrey ; Dasgupta, Asish ; Dunham-Snary, Kimberly ; Wu, Danchen ; Chen, Kuang Hueih ; Hong, Zhigang ; Sharp, Willard W. ; Kutty, Shelby ; Archer, Stephen L. / Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. In: Journal of Molecular Medicine. 2017 ; Vol. 95, No. 4. pp. 381-393.
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AU - Tian, Lian

AU - Neuber-Hess, Monica

AU - Mewburn, Jeffrey

AU - Dasgupta, Asish

AU - Dunham-Snary, Kimberly

AU - Wu, Danchen

AU - Chen, Kuang Hueih

AU - Hong, Zhigang

AU - Sharp, Willard W.

AU - Kutty, Shelby

AU - Archer, Stephen L.

PY - 2017/4/1

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N2 - 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.

AB - 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.

KW - Diastolic dysfunction

KW - Ischemia-reperfusion injury

KW - Mdivi-1

KW - Mitochondrial division inhibitor 1

KW - Mitochondrial membrane potential

KW - Pulmonary arterial hypertension

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