Vascular respiratory uncoupling increases blood pressure and atherosclerosis

Abstract

The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, a process that occurs to some extent in all cells and may be characteristic of blood vessels being predisposed to the development of atherosclerosis. To test the hypothesis that inefficient metabolism in blood vessels promotes vascular disease, we generated mice with doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall. Here we show that UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. UCP1 expression also increases superoxide production and decreases the availability of nitric oxide, evidence of oxidative stress. These results provide proof of principle that inefficient metabolism in blood vessels can cause vascular disease.

Increased Protein Nitration in Mitochondrial Diseases: Evidence for Vessel Wall Involvement

“…A blunted or absent increase in shear stress and NO-induced vasodilatation in peripheral arteries may result in increased vascular resistance and inadequate blood supply, further worsening the energetic imbalance in skeletal muscle because of ineffective ATP generation. Recent data from experimental models indicate that mitochondrial dysfunction is associated with cardiovascular alterations including increased blood pressure, atherosclerosis, and premature aging (32,33). Moreover, mtDNA mutations have been associated with increased blood pressure also in humans (34 -37).…”

N-Acetylcysteine Reduces the Severity of Atherosclerosis in Apolipoprotein E-Deficient Mice by Reducing Superoxide Production

“…1 We and other investigators had already reported that experimental atherosclerosis in apoE-deficient mice was markedly suppressed by the Fcγ portion of immunoglobulin administration, possibly by an antiinflammatory action via the inhibitory Fcγ receptor IIB. [19][20][21] There is also increasing evidence to support the critical role of both free radicals and oxidative stress in the development of atherosclerosis [22][23][24][25] and in heart failure. 26,27 We had already demonstrated that MCI-186, a free radical scavenger, and olmesartan, an angiotensin type 1 receptor antagonist, suppress the severity of experimental atherosclerosis.…”

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

“…Several enzymes have been implicated as possible sources of elevated ROS in hypertension, including NADPH oxidase, 14,15 xanthine oxidase, 16 NO synthase (NOS), 17 cyclooxygenase, 18 and mitochondrial electron transport leakage. 19 It has been suggested that reductions of enzymes that scavenge ROS, such as superoxide dismutases (SOD), 20 catalase, and glutathione peroxidase (GPx), may also play a role. In the present study, we explored which of these many pathways most importantly determines the susceptibility of the SS rat to salt-induced hypertension.…”