Redox Homeostasis in Cardiovascular Disease: The Role of Mitochondrial Sirtuins

Abstract

Cardiovascular disease (CVD) is still the leading cause of death worldwide. Despite successful advances in both pharmacological and lifestyle strategies to fight well-established risk factors, the burden of CVD is still increasing. Therefore, it is necessary to further deepen our knowledge of the pathogenesis of the disease for developing novel therapies to limit even more its related morbidity and mortality. Oxidative stress has been identified as a common trait of several manifestations of CVD and could be a promising target for innovative treatments. Mitochondria are a major source of oxidative stress and sirtuins are a family of enzymes that generate different post-translational protein modifications, thus regulating important cellular processes, including cell cycle, autophagy, gene expression, and others. In particular, three sirtuins, SIRT3, SIRT4, and SIRT5 are located within the mitochondrial matrix where they regulate energy production and antioxidant pathways. Therefore, these sirtuins are strongly involved in the balance between oxidant and antioxidant mechanisms. In this review, we summarize the activities of these sirtuins with a special focus on their role in the control of oxidative stress, in relation to energy metabolism, atherosclerosis, and CVD.

Keywords: ROS; cardiovascular disease; energy metabolism; mitochondria; sirtuins.

Figure 1

Molecular mechanisms underlying ROS production and the activity of mitochondrial sirtuins on CVD. SIRT3, 4, and 5 control cellular metabolism, and mitochondrial and ROS homeostasis. Dietary interventions, in the forms of fasting and calorie restriction, as well as physical exercise, stimulate SIRT3 and 5 and repress SIRT4. SIRT3 and 5 activate energy production and antioxidant pathways, resulting in the protection of the cardiovascular system, particularly during metabolic and oxidative stress. Differently, SIRT4 seems to have both a detrimental and a beneficial effect on the cardiovascular system. ACOX1, Acyl-CoA Oxidase 1; AMPK, AMP-Activated Protein Kinase; ANT2, Adenine Nucleotide Translocator 2; Bcl-XL, B-cell lymphoma extra-large; CASP-3/9; Caspase 3 and 9; CR, Calorie Restriction; COX, Cytochrome C Oxidase; CYPs, Cytochrome P450; ECHA, Enoyl-Coenzyme A Hydratase; FOXO2A, Forkhead Box O3A; G6PD, Glucose-6-Phosphate Dehydrogenase; GSH-Px, Glutathione peroxidase; IDH2, Isocitrate Dehydrogenase 2; IL1b, Interleukin 1 beta; IL6, Interleukin 6; IL8, Interleukin 8; IMS, intermembrane space; LCAD, Long-Chain Acyl-CoA Dehydrogenase; LOX, Lipoxygenase; MC-I, Mitochondrial Complex I; mTOR, Mammalian Target Of Rapamycin; MTX, Mitochondrial Matrix; NAM, Nicotinamide; NF-kB, Nuclear factor-kappa b; NOS, Nitric Oxide Synthases; NOX, NADPH Oxidase; OGG1, 8-oxoguanine-DNA glycosylase; OPA1, Optic Atrophy 1; Prx, Peroxiredoxin; PDH, Pyruvate Dehydrogenase; PKM2, Pyruvate Kinase M1/2; ROS, Reactive oxygen species; SDHA, Succinate Dehydrogenase Complex, subunit A; SOD, Superoxide Dismutase; XO, Xanthine oxidase.