Abstract 15847: Inhibition of Drp1-mediated Mitochondrial Fission Improves Diastolic Function in Right Ventricular Ischemia-reperfusion Injury
Introduction: Mitochondrial fission, regulated by the GTPase dynamin-related protein 1 (Drp1), contributes to impairment of left ventricular function following ischemia-reperfusion (IR) injury or cardiac arrest. Drp1 inhibition improves LV function in IR. The effects of IR on the right ventricle (RV) and the contribution of mitochondrial fission to impaired RV function following IR are unknown. We hypothesize that: a) IR activates Drp1 in RV myocytes leading to mitochondrial fission and RV dysfunction b) inhibiting Drp1 will improve RV function.
Methods: RV-IR was compared in control rats versus rats with monocrotaline-induced pulmonary arterial hypertension (MCT PAH). PAH was confirmed by measuring pulmonary artery acceleration time (PAAT), RV diastolic and systolic thickness (RVFW), and tricuspid annular plane systolic excursion (TAPSE) via ultrasound.
IR was created in RV Langendorff preparation using two cycles of 15 min of ischemia followed by 15 min of reperfusion. We investigated the effects of two Drp1 inhibitors on RV function following IR: Mdivi-1, an inhibitor of Drp1’s GTPase activity and P110, a peptide inhibitor of the interaction between Drp1 and its binding partner, fission protein 1 (Fis1).
Immunoblotting was performed on mitochondrial and cytosolic protein extracted from RV after Langendorff experiment to measure total and active Drp1 (defined as Drp1 in the mitochondria or phosphorylated at serine 616).
Results: Compared to control, MCT produced severe PAH in week 4 as indicated by reduced PAAT and TAPSE and increased RVFW thickness. IR increased RV end diastolic pressure (RVEDP) without impairing developed systolic RV pressure. Both Mdivi-1 and P110 reduced the rise of RVEDP in the PAH RV following IR, with P110 being more effective. At baseline, cytosolic Drp1 expression was lower and mitochondrial Drp1 expression was higher in PAH vs. control RV. With IR, mitochondrial Drp1 expression increased in normal RV.
Conclusions: The RV-IR response is characterized by isolated diastolic dysfunction and it results from Drp1 activation. Inhibition of mitochondrial fission, particularly by blocking the Drp1-Fis1 interaction, preserves RV diastolic function and may be a promising therapeutic strategy to improve RV function in PAH.
Author Disclosures: L. Tian: None. M. Feng: None. Z. Hong: None. W.W. Sharp: None. S. Kutty: None. S.L. Archer: Research Grant; Significant; I am PI on Grants from NIH, CFI, CIHR-all >$100,000/year.
- © 2015 by American Heart Association, Inc.