Protective role of the mitochondrial fusion protein OPA1 in hypertension

Abstract

Hypertension is associated with excessive reactive oxygen species (ROS) production in vascular cells. Mitochondria undergo fusion and fission, a process playing a role in mitochondrial function. OPA1 is essential for mitochondrial fusion. Loss of OPA1 is associated with ROS production and cell dysfunction. We hypothesized that mitochondria fusion could reduce oxidative stress that defect in fusion would exacerbate hypertension. Using (a) Opa1 haploinsufficiency in isolated resistance arteries from Opa1+/− mice, (b) primary vascular cells from Opa1+/− mice, and (c) RNA interference experiments with siRNA against Opa1 in vascular cells, we investigated the role of mitochondria fusion in hypertension. In hypertension, Opa1 haploinsufficiency induced altered mitochondrial cristae structure both in vascular smooth muscle and endothelial cells but did not modify protein level of long and short forms of OPA1. In addition, we demonstrated an increase of mitochondrial ROS production, associated with a decrease of superoxide dismutase 1 protein expression. We also observed an increase of apoptosis in vascular cells and a decreased VSMCs proliferation. Blood pressure, vascular contractility, as well as endothelium‐dependent and ‐independent relaxation were similar in Opa1+/−, WT, L‐NAME‐treated Opa1+/− and WT mice. Nevertheless, chronic NO‐synthase inhibition with L‐NAME induced a greater hypertension in Opa1+/− than in WT mice without compensatory arterial wall hypertrophy. This was associated with a stronger reduction in endothelium‐dependent relaxation due to excessive ROS production. Our results highlight the protective role of mitochondria fusion in the vasculature during hypertension by limiting mitochondria ROS production.

L-Arginine Improves Cognitive Impairment in Hypertensive Frail Older Adults

“…To mechanistically confirm our results, we examined in vitro the effects of L-Arginine on mitochondrial function in human endothelial cells, showing that L-Arginine significantly attenuates the generation of mitochondrial ROS induced by Ang II. Intriguingly, this finding is consistent with recent observations linking frailty and cognitive decline to mitochondrial dysfunction ( 66 – 68 ), which is also a well-recognized determinant of hypertension and vascular aging ( 69 – 72 ).…”

Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis

“…The occurrence of Opa1 haploinsufficiency in mesenteric arteries isolated from Opa1 + / − mice was demonstrated in our previous work showing a 69% Opa1 reduction in mesenteric resistance arteries [ 27 ]. Stepwise increases in flow rate in mesenteric resistance arteries induced a progressive dilation or FMD ( Figure 3 A).…”

“…The occurrence of metabolic stroke has also been observed in a patient with “ADOA plus syndrome” [ 26 ]. Finally, we have recently shown that the Opa1 +/− mouse is more susceptible to hypertension [ 27 ]. Thus, we investigated the role of mitochondrial fusion in FMD and cardiovascular disease development, with the perspective to position mitochondrial dynamics as a tractable therapeutic target [ 11 ].…”

Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence

“…As for the relationships among HTN, the vascular system, and mitochondrial dynamics, Opa1 knockdown was reported to induce apoptosis in VSMC. Administration of L-NAME, a nonselective inhibitor of nitric oxide synthase, to Opa1 heterozygous KO mice caused greater HTN compared to wild type ( 117 ). These in vitro and in vivo experiments indicate that Opa1 has a protective role against HTN by regulating endothelium-dependent relaxation to offset excessive ROS production.…”