期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 95, 期 4, 页码 381-393出版社
SPRINGER
DOI: 10.1007/s00109-017-1522-8
关键词
Ischemia-reperfusion injury; Pulmonary arterial hypertension; Diastolic dysfunction; Mitochondrial membrane potential; Mdivi-1; Mitochondrial division inhibitor 1
资金
- U.S. National Institutes of Health (NIH) [NIH R01HL113003, NIH R01HL071115, NIH 1R01HL133675-01]
- Canada Foundation for Innovation [229252, 33012]
- Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine [950-229252]
- William J. Henderson Foundation
- Canadian Vascular Network Scholar Award
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 mu M), a Drp1 GTPase inhibitor, and P110 (1 mu M), 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.
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