Abstract
There is growing focus on mitochondrial impairment and cardiovascular diseases (CVD) in type 2 diabetes (T2D), and the development of novel therapeutic strategies in this context. It is unknown whether mitochondrial-targeting antioxidants such as SS-31 protect sufficiently against oxidative damage in diabetes. We aimed to evaluate if SS-31 modulates SIRT1 levels and ameliorates leukocyte-endothelium interactions, oxidative stress and inflammation in T2D patients. Anthropometric and metabolic parameters were studied in 51 T2D patients and 57 controls. Production of mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, glutathione content, leukocyte-endothelium interactions, NFκB-p65, TNFα and SIRT1 levels was measured in leukocytes treated or not with SS-31. We observed increased mitochondrial ROS production that was restored by SS-31 treatment. SS-31 also increased mitochondrial membrane potential, glutathione content, SIRT1 levels and leukocyte rolling velocity and reduced rolling flux and adhesion in T2D patients. NFκB-p65 and TNFα, which were enhanced in diabetic patients, were also reduced by SS-31 treatment. Our results reveal that SS-31 exerts beneficial effects on the leukocytes of T2D patients by reducing oxidative stress, leukocyte-endothelium interactions, NFκB and TNFα and by increasing SIRT1 levels. These actions support its use as a potential agent against CVD risk.
Highlights
Type 2 diabetes (T2D) is an increasingly prevalent disease and a serious health problem worldwide, as it can markedly reduce life expectancy[1,2]
In the present study we have observed that a series of parameters that are altered by type 2 diabetes (T2D) - oxidative stress, mitochondrial membrane potential and SIRT1, leukocyte-endothelial interactions and NFκB and TNFα levels in leukocytes - are restored by the mitochondrial-targeted antioxidant SS-31, highlighting its potential as an agent in the treatment of T2D
The pathophysiology of T2D involves a series of systemic interrelated alterations including oxidative stress, mitochondrial dysfunction and inflammation
Summary
Type 2 diabetes (T2D) is an increasingly prevalent disease and a serious health problem worldwide, as it can markedly reduce life expectancy[1,2]. It has been demonstrated that the nuclear factor kappa B (NFκB), a central regulator of immunity, inflammation and cell survival, is activated under these conditions[14,15,16]. This inflammatory state involves an enhanced adhesion of leukocytes to the surface of the endothelium, after which they migrate in order to destroy pathogens by generating production of ROS. Given that enhanced ROS production under oxidative stress contributes to the mitochondrial injury that promotes endothelial dysfunction and, in turn, leukocyte adhesion, inflammation, thrombosis and smooth muscle cell proliferation[17], the search for novel therapies that ameliorate mitochondrial oxidative stress in metabolic diseases such as T2D is paramount
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