Red wine acts through a familiar drug target

Abstract

Resveratrol, a natural polyphenol first identified and named by a Japanese chemist in 1940 [1], is present in many plant products, including grape skin. It has been the focus of much attention recently because it provides a variety of potential health benefits, in particular protection from various age-related conditions (such as diabetes mellitus, vascular diseases, cognitive disorders, and cancer), and increases life span [2–4]. Given that red wine is rich in resveratrol, and that moderate wine consumption has been shown to lower cardiovascular risk [5], the intake of resveratrol through the drinking of red wine may contribute to the ‘‘French paradox’’—which refers to the fact that the mortality due to cardiovascular diseases is lower in France than in other European countries despite similar lifestylerelated risk factors [6]. Sirt1, an NAD-dependent protein deacetylase, is thought to play an important role in the action of resveratrol [2]. Resveratrol stimulates the activity of Sirt1, and overexpression of Sirt1 protects mice from age-related diseases [2]. Moreover, orthologs of Sirt1 appear to contribute to life span extension by resveratrol in worms and flies [2]. Whereas an early study suggested that resveratrol directly stimulates the activity of Sirt1 [7], this notion has been challenged by more recent studies [8, 9]. Resveratrol was found to stimulate the activity of AMPactivated protein kinase (AMPK) [10], which can increase cellular NAD levels and thereby stimulate the activity of Sirt1 [11], but the effect of resveratrol on AMPK is also likely not direct. The direct target of resveratrol for its health-promoting effects has thus remained a mystery. Park et al. [12] have now revealed that a group of enzymes that serve as common drug targets are also targeted by resveratrol. The cyclic nucleotides cAMP and cGMP are both important messenger molecules in intracellular signaling. An increase in the cellular levels of cAMP and cGMP is achieved through their synthesis by adenylyl cyclase and guanylyl cyclase, respectively. Conversely, the levels of these molecules are reduced through their hydrolysis by phosphodiesterases (PDEs). Mammalian PDEs constitute a large family of enzymes that are categorized into 11 subtypes (PDE1 to PDE11) encoded by 21 different genes [13]. Individual PDEs differ in their affinity for substrates, tissue distribution, and mode of regulation, and together they share a broad range of biological tasks [13]. Various pharmacological inhibitors of PDEs have been developed, some of which are marketed as drugs for a wide variety of conditions, including bronchial asthma (theophylline), peripheral artery disease (cilostazol), heart failure (amrinone), cognitive disorders (vinpocetine), depression (rolipram), and erectile dysfunction (sildenafil, vardenafil, and tadalafil) [13]. Park et al. [12] have now shown that resveratrol inhibits the activity of several PDEs (PDE1, -3, and -4, but not -2 or -5) in vitro by directly competing with cAMP to bind to these isozymes (Fig. 1). Inhibition of PDEs results in an increase in cellular cAMP levels and the consequent activation of two signaling pathways: the cAMP-dependent protein kinase (PKA) pathway and the Epac1 (exchange protein directly activated by cAMP 1) pathway [14]. Park et al. [12] found that both Sirt1 and AMPK were activated by resveratrol in a manner dependent on Epac1, consistent with the notion that the cellular accumulation of cAMP, likely due to PDE inhibition, is the primary cellular event triggered by resveratrol. Calciumand calmodulinW. Ogawa (&) T. Hosooka Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan e-mail: ogawa@med.kobe-u.ac.jp