Vascular inflammation, oxidative stress, and lipid deposition are prominent features of atherosclerotic lesion development.We found that the dithiol compound, á-lipoic acid, exerts strong anti-inflammatory effects by inhibiting TNFá- and LPS-induced endothelial and monocyte activation in vitro and LPS-induced acute inflammatory responses in vivo. These effects of lipoic acid were mediated mainly by activation of the phosphoinositide 3-kinase/Akt signaling pathway, resulting in inhibition of NFêB activation. We also investigated whether lipoic acid inhibits atherosclerosis in two well-established murine models of atherosclerosis. To this end, four-week old female apolipoprotein E-deficient (apoE-/-) mice were fed a Western-type chow diet containing 15% fat and 0.125% cholesterol without or with 0.2% R,S-á-lipoic acid; or apoE and low-density lipoprotein receptor-deficient (apoE/LDLR-/-) mice were fed a normal chow diet containing 4% fat without or with 0.2% R-á-lipoic acid. After ten weeks of feeding, lipoic acid significantly attenuated atherosclerotic lesion formation in the aortic sinus of both mouse models by 20%, and in the aortic arch and thoracic aorta of apoE-/- mice and apoE/LDLR-/- mice, respectively, by 55% and 40%. These anti-atherogenic effects of lipoic acid were associated with significantly less body weight gain; lower serum levels of triglycerides, but not cholesterol; reduced aortic expression of pro-inflammatory adhesion molecules and cytokines; and less aortic macrophage infiltration. Our data suggest that lipoic acid may be useful in the prevention and treatment of atherosclerotic vascular diseases and other inflammatory conditions, and may exert additional health benefits in humans.
Execution of apoptotic program interrupts monotonous electron-shuttling (between mitochondrial complexes III and IV) activity of cytochrome c. We discovered that this is due to
its interactions with cardiolipin (CL) resulting in a new catalytic functions of cyt c as a CL oxygenase that is activated during apoptosis and causes selective oxidation of CL. Trans-membrane migration of CL from the inner to the outer mitochondrial membrane early in apoptotsis makes the interaction possible. The oxidized CL is required for the release of pro-apoptotic factors from mitochondria into the cytosol. In CL-deficient cells (via RNAi knocking down of CL synthase) form less productive cyt c/CL complexes, display suppressed CL oxidation, and exert enhanced resistance to pro-apoptotic stimuli. Bax/Bak participate in the regulation of cyt c/CL pperoxidase activity. This redox mechanism of cyt c is realized earlier than its other well-recognized functions in programmed cell death pathways - formation of apoptosomes and caspase activation. CL acts as a redox switch that turns off the electron transporting function of cyt c and turns on its peroxidase activity. Mitochondria-targeted inhibitors of CL peroxidation (eg, hemigramicidin conjugates with nitroxides) act as potent anti-apoptotic agents thus offering new opportunities for drug discovery. In the cytosol, released cyt c interacts with another anionic phospholipid, phosphatidylserine (PS), and catalyzes its oxidation in a similar oxygenase reaction. Peroxidized PS facilitates its externalization essential for the recognition and clearance of apoptotic cells by macrophages. Redox catalysis of plasma membrane PS oxidation constitutes an important redox-dependent function of cyt c in apoptosis and phagocytosis. Thus, cyt c acts as an anionic phospholipid specific oxygenase activated and required for the execution of essential stages of apoptosis.
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11:00 a 11:30 - Young Investigator Award and Closing
12:00 a 13:00 - Farewell Reception in the Teatro Solís