Dynamin-related protein 1–mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in …

G Marsboom, PT Toth, JJ Ryan, Z Hong, X Wu… - Circulation …, 2012 - Am Heart Assoc
G Marsboom, PT Toth, JJ Ryan, Z Hong, X Wu, YH Fang, T Thenappan, L Piao, HJ Zhang…
Circulation research, 2012Am Heart Assoc
Rationale: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by
pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell
(PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-
inducible factor-1α (HIF-1α) have been observed in PAH PASMCs; however, their
relationship and relevance to the development of PAH are unknown. Dynamin-related
protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine …
Rationale:
Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1α (HIF-1α) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation.
Objective:
We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential.
Methods and Results:
Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1α activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1α activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1–dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1α activation by CoCl2 or desferrioxamine causes DRP1-mediated fission. HIF-1α inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH.
Conclusions:
DRP-1–mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.
Am Heart Assoc