Bioaccumulation of resveratrol metabolites in myocardial tissue is dose-time dependent and related to cardiac hemodynamics in diabetic rats
Introduction
Resveratrol (RSV: trans-3,5,4′-trihydroxystilbene) is a natural compound occurring in different foods and plants, such as red wine, grapes, peanuts, pistachios and berries [1].
Over recent decades, a number of studies have linked RSV consumption to beneficial and protective effects on human health. In particular, RSV has been described as an antioxidant, modulator of lipoprotein metabolism, inhibitor of platelet aggregation, vasorelaxant and cancer chemopreventive [2], [3]. It is also considered a potentially effective therapeutic adjuvant to prevent the occurrence of cardiovascular complications in both type 1 and type 2 diabetes [4], [5], [6], [7]. In addition to antioxidant, antiapoptotic/anti-inflammatory effects, RSV may possess several other cardio-protective roles due to a wide range of direct and indirect target molecules mediating its biological actions, including the modulation of enzymes, cell signaling pathways and gene expression [5], [7], [8], [9], [10], [11], [12].
Despite a wide body of experimental evidence indicating that RSV can have positive effects on the diabetic heart, leading to functional and structural recovery, proof of efficacy of RSV in humans has been more elusive and to date there is a paucity of convincing human studies, pertaining to cardiovascular disease prevention or treatment [5], [13]. The current evidence base does not justify the therapeutic administration of RSV to humans, beyond that which can be achieved via dietary sources [13]. Major challenges remain, concerning the safety and efficacy of chronic RSV administration as well as optimal doses, due to the well-known hormetic actions of the compound, which demonstrates cardio-protective properties at lower doses and detrimental effects at higher doses [14]. When considering the potential future use of RSV in the clinical setting, to prevent and/or treat cardiovascular complications of diabetes such as cardiomyopathy, a number of issues remain to be addressed. An expanding body of preclinical evidence has been largely focused on characterizing the pharmacokinetics and metabolism of RSV. However, the effects of time and doses on cardiac tissue distribution as well as excretion of RSV and its main structurally-related metabolites remain limited.
Although several studies have already demonstrated the ability of RSV to protect against several diseases [15], some questions arise due to its low bioavailability [2], due to rapid metabolism, following oral absorption [16]. In animals and humans, at enterocyte and hepatocyte levels, RSV is rapidly metabolized [16] and conjugated with glucuronic acid and sulfate due to the action of UDP-glucuronosyl-transferases and sulfotransferases [17] and these are the major circulating forms of this molecule. However, the biological activity of these metabolites formed in humans and experimental animals needs to be elucidated fully. There is a lack of studies investigating organ, fluid and tissue distribution of RSV and its metabolites with the exception of some work in normal rodents [18], [19], [20], [21], rabbits [22] and pigs [23], [24].
Particularly, little is known about the heart tissue distribution of RSV and its active metabolites after chronic treatment with different doses of the compound [20]. This preliminary knowledge is required to perform “in vitro” mechanistic studies aimed at reliably defining the molecular pathways underlying the “in vivo” measured effects of the compound, and the possible combined effects of chronic exposure to RSV with other well characterized bioactive compounds. Indeed, the majority of “in vitro” available data have been obtained by employing the un-conjugated form of RSV, at concentrations which largely exceed those that can be reached in vivo, at both plasma and tissue levels [25].
In the present study we specifically addressed these issues, in a rat model of type-1 diabetes induced by Streptozotocin injection [26], with a view to defining, for the first time, the distribution of RSV and its active metabolites in myocardial tissue after short and medium-term treatment with the compound, at different low doses. Dose-time dependent effects of RSV administration on glycemic control and functional properties of the diabetic heart have also been assessed.
Section snippets
Methods
The investigation was approved by the Veterinary Animal Care and Use Committee of the University of Parma-Italy and conforms to the National Ethical Guidelines of the Italian Ministry of Health (Permit number: 41/2009-B) and the Guide for the Care and Use of Laboratory Animals (National Institute of Health, Bethesda, MD,USA, revised 1996). All surgery was performed under ketamine chloride anesthesia, and all efforts were made to minimize suffering.
Tissue and urine distribution study of RSV and active metabolites
An example of UHPLC traces and mass spectra of RSV sulfate detected in heart samples and a comparison with the pure standard is reported (Fig. 1).
Concerning RSV sulfate recovered in rat hearts, no dose of RSV led to bioaccumulation in myocardial tissue after the first week of treatment. Starting from 3 weeks of RSV administration, low concentrations of RSV metabolites were recovered in the heart of animals treated with 5 mg/kg/day (Fig. 2A). After 6 weeks of treatment the RSV sulfate myocardial
Discussion
Despite the vast literature on RSV cardioprotective action, little is known about the heart tissue distribution of RSV and its active metabolites after chronic treatment with different doses of the compound. To our knowledge, this is the first study where RSV metabolite accumulation in diabetic rat heart after a short-term (1 week) and medium-term exposure (3–6 weeks) to different doses of RSV has been investigated in relation to specific functional beneficial effects.
RSV is a stilbene with a
Acknowledgments
This study has been partly supported by “Progetto AGER” (grant no. 2011-0283) and by the National Institute for Cardiovascular Research (INRC).
References (37)
- et al.
In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota
Am J Clin Nutr
(2013) - et al.
Bioactive compounds in wine: resveratrol, hydroxytyrosol and melatonin: a review
Food Chem
(2012) - et al.
Cardiovascular effects and molecular targets of resveratrol
Nitric Oxide
(2012) - et al.
The protective effect of resveratrol on islet insulin secretion and morphology in mice on high-fat diet
Diabetes Res Clin Pract
(2012) - et al.
Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism
J Biol Chem
(2011) - et al.
Quantification of trans-resveratrol and its metabolites in rat plasma and tissues by HPLC
J Pharm Biomed Anal
(2010) - et al.
Inhibition of cancer growth by resveratrol is related to its low bioavailability
Free Radic Biol Med
(2002) - et al.
Pharmacokinetics, tissue distribution and excretion study of resveratrol and its prodrug 3,5,4′-tri-O-acetylresveratrol in rats
Phytomedicine
(2013) - et al.
Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase
Free Radic Biol Med
(2007) - et al.
Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose
J Nutr Biochem
(2009)
Bioavailability of resveratrol
Ann N Y Acad Sci
Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy
Am J Physiol Heart Circ Physiol
Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants
Heart Fail Rev
Resveratrol improves left ventricular diastolic relaxation in type 2 diabetes by inhibiting oxidative/nitrative stress: in vivo demonstration with magnetic resonance imaging
Am J Physiol Heart Circ Physiol
Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2
Am J Physiol Heart Circ Physiol
Resveratrol in cardiovascular health and disease
Ann N Y Acad Sci
Resveratrol treatment reduces cardiac progenitor cell dysfunction and prevents morpho-functional ventricular remodeling in type-1 diabetic rats
PLoS One
What is new for an old molecule? Systematic review and recommendations on the use of resveratrol
PLoS One
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These authors equally contributed to this work.