TY - JOUR
T1 - Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension
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.
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/4/1
Y1 - 2017/4/1
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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U2 - 10.1007/s00109-017-1522-8
DO - 10.1007/s00109-017-1522-8
M3 - Article
C2 - 28265681
AN - SCOPUS:85014546304
SN - 0946-2716
VL - 95
SP - 381
EP - 393
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 4
ER -