Coenzyme Q10 and diabetic endotheliopathy: oxidative stress and the 'recoupling hypothesis'

Abstract

Increased oxidative stress in diabetes mellitus may underlie the development of endothelial cell dysfunction by decreasing the availability of nitric oxide (NO) as well as by activating pro-inflammatory pathways. In the arterial wall, redox imbalance and oxidation of tetrahydrobiopterin (BH4) uncouples endothelial nitric oxide synthase (eNOS). This results in decreased production and increased consumption of NO, and generation of free radicals, such as superoxide and peroxynitrite. In the mitochondria, increased redox potential uncouples oxidative phosphorylation, resulting in inhibition of electron transport and increased transfer of electrons to molecular oxygen to form superoxide and other oxidant radicals. Coenzyme Q10 (CoQ), a potent antioxidant and a critical intermediate of the electron transport chain, may improve endothelial dysfunction by 'recoupling' eNOS and mitochondrial oxidative phosphorylation. CoQ supplementation may also act synergistically with anti-atherogenic agents, such as fibrates and statins, to improve endotheliopathy in diabetes.

Antioxidants, Diabetes, and Endothelial Dysfunction

“…23,24 With increased oxidative stress, tetrahydrobiopterin (BH4), a co-factor that regulates NO production tightly, is oxidized resulting in the uncoupling of eNOS and reduced NO production. 25 Elevated levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS through competition with L-arginine, may further reduce NO production. 26 This perpetuates a cycle of vascular oxidative stress through the transfer of electrons to molecular oxygen, forming oxidant species such as superoxide and peroxynitrite, which further consume NO and increase oxidative stress, leading to endothelial dysfunction.…”

“…26 This perpetuates a cycle of vascular oxidative stress through the transfer of electrons to molecular oxygen, forming oxidant species such as superoxide and peroxynitrite, which further consume NO and increase oxidative stress, leading to endothelial dysfunction. 25,27 …”

Effect of coenzyme Q10 on depression paradigms in male Wistar rats and Swiss albino mice

“…A small quantity is acquired through dietary sources such as oily fish, organ meats (liver), and whole grains. [13,16] CoQ10 has found to have clinical applications in the treatment of hypertension, cardiac failure, statin-induced myopathy, Parkinson's and Huntington's diseases, and Friedreich's ataxia. [17] The evidence generated by this study, on the antidepressant activity of CoQ10 adds further weightage to the existing literature on the antidepressant activity of CoQ10 by testing parameters which are different from those of the remaining studies.…”

Vascular failure and recent anti-diabetic drugs

“…Tetrahydrobioptein (BH4) binds to NOS as a cofactor and suppresses superoxide production 9) . However, insufficient BH4 directs NOS to produce superoxide rather than NO 10) , and increased oxidative stress can oxidize BH4, resulting in the uncoupling of eNOS and reduced NO production 11,12) . Moreover, the absence of BH4 increases oxidative stress through transfer of electrons to molecular oxygen, forming oxidant species that further consume NO and increase oxidative stress 7,11,12) .…”

“…However, insufficient BH4 directs NOS to produce superoxide rather than NO 10) , and increased oxidative stress can oxidize BH4, resulting in the uncoupling of eNOS and reduced NO production 11,12) . Moreover, the absence of BH4 increases oxidative stress through transfer of electrons to molecular oxygen, forming oxidant species that further consume NO and increase oxidative stress 7,11,12) . Given that superoxide converts NO into peroxynitrite, generates hydroxyl radicals, and injures cells, the balance of production and the existence of NO, superoxide, and related factors in vascular endothelial cells play important roles in vascular endothelial injury.…”