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

• DOI: 10.1007/s00109-017-1522-8
• Publication Date: 2017-03-06T18:31:47Z
• Authors: Lian Tian; Monica Neuber-Hess; Jeffrey Mewburn; Asish Dasgupta; Kimberly Dunham-S...; Danchen Wu; Kuang-Hueih Chen; Zhigang Hong; Willard W. Sharp; Shelby Kutty; Stephen L. Archer
• Keywords: Dynamins; RM; 0303 health sciences; Hypertension, Pulmonary; Ventricular Dysfunction, Right; 610; Myocardial Reperfusion Injury; 612; Mitochondrial Dynamics; Mitochondria; Mitochondrial Proteins; Rats, Sprague-Dawley; 03 medical and health sciences; Animals; Therapeutics. Pharmacology

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.