A glass of red wine to improve mitochondrial biogenesis? Novel mechanisms of resveratrol.

NUMEROUS EPIDEMIOLOGICAL studies demonstrated an association between moderate alcohol consumption and reduced coronary heart disease. Red wine, especially, is shown to be protective against numerous cardiovascular and metabolic diseases. Frankel et al. (5) demonstrated that red wine polyphenols inhibited the oxidation of low-density lipoprotein more than did the established antioxidant a-tocopherol. Resveratrol (3,5,4 -trihydroxystilbene) is known to be a component of some plants of medicinal use like Polygonum cuspidatum, a plant used in traditional medicine. Resveratrol, initially characterized as phytoalexin, attracted much attention in 1992 when it was postulated to explain the cardioprotective role of red wine. Resveratrol and its analogs have been investigated in numerous trials over a couple of decades reporting in vitro and in vivo beneficial effects of these compounds in a variety of human disease models, such as cardioand neuroprotection, immune regulation, and cancer chemoprevention. These studies have underscored the high degree of diversity in terms of the signaling networks and cellular effector mechanisms impacted by resveratrol. Among them are cell surface receptors, membrane signaling pathways, intracellular signal transduction machinery, nuclear receptors, gene transcription, and metabolic pathways. The promise shown by resveratrol has prompted heightened interest in studies aimed at translating these observations to the clinical settings. There is accumulating evidence that resveratrol can exert antioxidant effects in biological systems via multiple direct and indirect mechanisms, including effects on reactive oxygen species (ROS) and nitric oxide (NO) production, lipid peroxidation, and endogenous antioxidant systems, all of which may contribute to the cardiovascular benefits of the compound (2). The multifaceted anti-inflammatory effects of resveratrol are not restricted to the increase of NO bioavailability and antioxidative properties. In various inflammatory disease models (such as ischemia-reperfusion, sepsis, etc.), a key step of tissue injury is the increase of leukocyte adherence and vascular transmigration into the injured tissue microcirculation (9). A recent study has demonstrated that intravenous administration of resveratrol attenuates these deleterious effects of ischemiareperfusion (9). Importantly, resveratrol may also confer vasculoprotection by regulating the expression of proinflammatory and proatherogenic genes in endothelial cells. Local leukocyte recruitment into the vessel wall is controlled by the expression of cell adhesion molecules. It is significant that resveratrol was shown in vitro to decrease endothelial VCAM and ICAM-1 expression and attenuate monocyte adhesiveness to the endothelium (4). Several lines of evidence suggest that inhibition of NFB by resveratrol underlies many of the anti-inflammatory effects of resveratrol (6). It has been proposed that high levels of inflammatory cytokines (in particular TNF) play a role in the development of cardiac and vascular dysfunction. Numerous studies demonstrated that increased levels of ROS may activate NFB in endothelial, smooth muscle cells, and other cell types, leading to the upregulation of adhesion molecules, inducible NO synthase (iNOS), TNF, and other cytokines. Importantly, resveratrol treatment significantly decreases iNOS expression in different cell types (3). A second proinflammatory transcription factor, activator protein 1 (AP-1), may also be inhibited by resveratrol (6). AP-1, similarly to NFB, is important in the regulation of many inflammatory genes that are induced by oxidative stress, and its inhibition may contribute to the antiinflammatory properties of resveratrol. Recently, resveratrol has been shown to have positive effects on age longevity and lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by upregulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4, and TRAIL-R2/DR5 and simultaneously downregulating the expression of Bcl-2, Bcl-XL, Mcl-1, and survivin. Resveratrol causes growth arrest at the G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and NFB activity. Modulation of the cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents, and -radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are the liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation, and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression (8). Although many possible pathways are already shown to be responsible to the beneficial actions, Csiszar et al. (1) could demonstrate novel mechanisms of resveratrol at the mitochondrial level. They identify resvertarol as a potent activator of mitochondrial biogenesis in coronary arterial endothelial cells (CAECs). An important recent paper published by the same authors in Cell Metabolism (7) raised the therapeutic possibility of resveratrol against both diabetes-induced and age-related vascular pathophysiological alterations. In the current article, the authors provide a very careful evaluation of the signaling cascades activated by resveratrol in endothelial cells, using both in vitro and in vivo (mouse models) approaches. First, they show that in CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated expression of electron transport chain constituents, and induced the mitochondrial biogenesis factors proliferator-activated receptorAddress for reprint requests and other correspondence: G. Szabó, Dept. of Cardiac Surgery, Univ. of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, 69120 Germany (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 297: H8–H9, 2009; doi:10.1152/ajpheart.00471.2009.