Home > Science Seminar > Spring 2010 > Dikalov
The Science Seminar Series: February 25, 2010
Role of Mitochondrial Dysfunction in Cardiovascular Diseases
Sergey Dikalov, PhD
Director of Free Radical in Medicine Core, Assistant Professor of Medicine
Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
Powell HallTime: 4:00 -5:00pm
Mitochondria are not just an ATP cow. They are recognized regulators of cell death in and remodeling process. Mitochondrial dysfunction is associated with cardiovascular diseases (CVD) however the exact role of mitochondria is not clear. Inherited and sporadic mitochondrial diseases caused by mutations to mitochondrial genes in mitochondrial or nuclear DNA are well documented. Meanwhile, mitochondrial dysfunction can be a source and course of oxidative stress. Mitochondria and NADPH oxidases are important sources of vascular reactive oxygen species (ROS) such as O2• and H2O2. Overproduction of ROS may results in decreased bioavailability of nitric oxide (NO•) and endothelial dysfunction. We have found that stimulation of endothelial cells with angiotensin II (AngII) increases production of mitochondrial ROS and impairs mitochondrial respiration. Depletion of p22phox subunit of NADPH oxidase with siRNA inhibits AngII-induced mitochondrial dysfunction. Inhibition of mitochondrial mitoKATP or reverse electron flow diminishes mitochondrial ROS, decreases activity of NADPH oxidase and increased endothelial NO•. We suggest that AngII induced O2• production by NADPH oxidase stimulates production of mitochondrial O2• that in turn provides redox dependent feed forward stimulation of NADPH oxidase. This vicious cycle can be interrupted at the mitochondrial site by mitochondria targeted antioxidants. We have developed a mitochondria-targeted SOD mimetic, mitoTEMPO, by conjugating the lipophilic triphenylphosphonium cation to an antioxidant moiety TEMPO. As expected, inhibition of mitochondrial oxidative stress with SOD2 overexpression or supplementation with mitoTEMPO attenuates endothelial oxidative stress, restores NO• production, improves endothelium-dependent vasodilatation and reduces blood pressure in AngII infused mice. The upstream activators and downstream targets of mitochondrial oxidative stress and their potential role in cardiovascular disease will be discussed.