Resveratrol in Relation to Cardiometabolic Risk and Disease: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Melania Gaggini
,
Simona Fenizia
,
Cristina Vassalle

Resveratrol (RSV) is a phenolic compound with strong antioxidant activity, which is generally associated with the beneficial effects of wine on human health. All resveratrol-mediated benefits exerted on different systems and pathophysiological conditions are possible through resveratrol’s interactions with different biological targets, along with its involvement in several key cellular pathways affecting cardiometabolic (CM) health. With regard to its role in oxidative stress, RSV exerts its antioxidant activity not only as a free radical scavenger but also by increasing the activity of antioxidant enzymes and regulating redox genes, nitric oxide bioavailability and mitochondrial function. RSV effects are mediated by changes in sphingolipids, a class of biolipids emerging as critical determinants of CM risk and disease. 

  • resveratrol
  • sphingolipids
  • ceramides
  • cardiometabolic health

1. Preclinical Studies

RSV exerts antioxidant, anti-inflammatory, antifibrotic and cardiometabolic protective properties [1]. Moreover, it reduces platelet aggregation, enhances vasodilation (and nitric oxide bioavailability), reduces endothelial activation and modulates the metabolism of glucose and lipids.
All these beneficial cardiometabolic RSV-related effects are mediated by different molecular targets, some of which have already been identified (e.g., the activation of sirtuin 1 and AMPK, as well as the inhibition of NfκB) (Table 1) [1]. A further possible mechanism that RSV uses to modulate endothelial function has been identified in the inhibition of the Pin1/Notch1 signaling pathway [2]. Nevertheless, it is known that RSV acts as an SIRT1 activator, decreasing vascular oxidative stress and preventing endothelial dysfunction [3]. In an in vitro model, the upregulation of SIRT1 appeared as a key factor for the activity of RSV in providing antiglycative/antioxidative defense and protection against high-glucose damage [4].
In two different in vitro models (rat aortic rings and human umbilical vein endothelial cells (HUVEC)), RSV was demonstrated to reduce both the acute high-glucose-induced endothelium-dependent relaxation damage induced by acetylcholine in phenylephrine-precontracted vessels, as well as cytotoxicity and oxidative stress, through a mechanism involving ROS scavenging, and was found to likely increase NO bioavailability [5]. The expression of antioxidant enzymes and endothelial-type nitric oxide synthase (eNOS) and reduction in the expression of inflammatory mediators are modulated by RSV through FoxO/SIRT1 activation and NRF2-dependent transcription [6]. Indeed, animal studies confirmed the beneficial effects of RSV supplementation on NO (circulating NO metabolites, eNOS expression, eNOS phosphorylation and eNOS uncoupling), generally in parallel to an improvement in blood pressure [7].
Moreover, RSV supplementation modulates the expression of different genes related to inflammation (INF-γ and TNF-α) and oxidative stress (heme oxygenase-1 and nitric oxide synthase) in the rat heart [8].
In rats, the administration of RSV (30 mg/kg·bw/daily for 10 weeks) reduced liver steatosis, oxidative stress and inflammation, improving the lipid profile as well as insulin sensitivity. It also reverted alterations in the hepatic mRNA expression levels of genes related to lipid metabolism and insulin signaling [9]. Moreover, RSV was shown to preserve β-cell function through the inhibition of the activity of phosphodiesterase, which hydrolyzes the phosphodiester bonds of cAMP and cGMP, thereby modulating various cellular signaling pathways [10]. Recent data also demonstrated that RSV reduces autophagy-mediated β-cell death via the inhibition of the CXCL16/ox-LDL pathway [11].
Other studies indicated that RSV reduces the apoptosis and modulates the paracrine function of cardiac microvascular endothelial cells under ischemia/reperfusion conditions [12]. In addition, RSV inhibits ox-LDL-induced endothelial injury (through the downregulation of circ_0091822 to upregulate miR-106b-5p-related TLR4) [13]. Ex vivo results on adipose tissue revealed that RSV inhibits adipogenesis through the activation of the AMPK-SIRT1-FOXO1 signaling pathway [14][15]. Moreover, RSV reduces the accumulation of triglycerides through the activation of PPARγ and SIRT1 [16][17].
Increasing evidence also highlights an important effect of RSV on the modulation of microbiota composition (type 2 diabetic animals and patients), similar to those induced by anti-diabetic drugs such as metformin, thus resulting in beneficial effects for T2D patients [18].

2. Clinical Studies

RSV supplementation had beneficial effects on some outcomes, such as blood pressure, the lipid profile, glycemic control and insulin resistance in T2D; the waist circumference in metabolic syndrome (MS); and body weight and inflammation markers in nonalcoholic fatty liver disease (NAFLD) [19]. In fact, it also improves insulin resistance and the glycolysis pathway, likely by modulating SIRT2, as evidenced using polycystic ovary syndrome granulosa cells [20]. Moreover, a meta-analysis of randomized controlled studies indicated that RSV is able to improve the lipid profile, reducing the TC, TG and LDL-C levels [21]. A meta-analysis of 25 studies (1171 participants, with 578 in the placebo group and 593 in the intervention group) demonstrated the benefits of RSV intake on lipid and glucose metabolism, with significant decreases in waist circumference, hemoglobin A1c, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol following RSV administration, exhibiting its major clinical value for obese and T2D patients [22]. Another recent meta-analysis of randomized controlled trials reported that RSV significantly enhances endothelial function, improving the flow-mediated dilation and intercellular adhesion molecule 1 (ICAM-1) levels [23].
An effect of resveratrol on mitochondrial function has been demonstrated in human muscle samples, which may constitute a beneficial effect in regard to cardiovascular disease (CVD) as well as the vascular and cardiac muscle, mitochondrial dysfunction being a general problem in CVD, in which different damaging processes can cause exhaustion that RSV may postpone [24].
RSV takes part in such a wide range of biological activities that it remains difficult to define its entire spectrum of actions. Moreover, many aspects need to be further evaluated, including the definition of an RSV threshold above which its effects are ensured, this also being the case for other variables that need to be taken into account (e.g., the durations of supplementation and the effects elicited, the RSV source (always being careful to avoid adverse effects derived from excessive alcohol consumption), age, the absorption and metabolism of RSV and other dietary components, but also individual genetic and gut microbiota characteristics) [8].
The recent available data essentially focus on the metabolic benefits of RSV in the context of obesity and T2D. In a meta-analysis including 11 randomized controlled trials (388 subjects), RSV significantly reduced fasting glucose, insulin, HbA1C and insulin resistance in T2D patients [25]. However, no significant effects of RSV on glycemic status were observed in the nondiabetic subjects [25]. Thus, further studies need to be planned based on the general population in order to evaluate the potential benefits of RSV in humans (e.g., the prevention of weight gain and metabolic dysfunction).
The combination of RSV with other substances may also be more effective in the treatment or prevention of cardiometabolic diseases, this being a strategy that is currently under evaluation based on subjects with metabolic syndrome, T2D or obesity (e.g., hesperetin; δ-Tocotrienol; a combination of curcumin, RSV, zinc, magnesium, selenium and vitamin D) [26][27][28][29].
Moreover, synthetic nano-systems or biologically derived carriers may incapsulate RSV, enhancing its physicochemical properties and targeted delivery, thus opening up a wide range of applications, including the CM setting [30].
Table 1. Main resveratrol pathways and effects involved in cardiometabolic benefits.
Pathways and Effects References
SIRT1 activation, AMPK activation, Pin1/Notch1 inhibition [2][14][15][20]
Modulation of the expression of antioxidant genes [6]
Anti-inflammatory effects
(e.g., NFκB inhibition)		 [1][6][8][9]
Improvement of endothelial function,
nitric oxide bioavailability, protection against LDL-ox		 [3][7][13][22]
Improvement of insulin sensibility, reduction in insulin resistance [9][23]
Glucose uptake and improvement of glucose metabolism [31][32][33]
Prevention of β-cell dysfunction and death [10][11]
Adipogenesis inhibition
(AMPK-SIRT1-FOXO1)		 [14][15]
Improvement of lipid metabolism [21]
Improvement of blood pressure [7]
Favorable microbiota composition [18]

This entry is adapted from the peer-reviewed paper 10.3390/antiox12051102

References

  1. Voloshyna, I.; Hussaini, S.M.; Reiss, A.B. Resveratrol in Cholesterol Metabolism and Atherosclerosis. J. Med. Food 2012, 15, 763–773.
  2. Yu, G.-H.; Fang, Y. Resveratrol Attenuates Atherosclerotic Endothelial Injury through the Pin1/Notch1 Pathway. Toxicol. Appl. Pharmacol. 2022, 446, 116047.
  3. Ciccone, L.; Piragine, E.; Brogi, S.; Camodeca, C.; Fucci, R.; Calderone, V.; Nencetti, S.; Martelli, A.; Orlandini, E. Resveratrol-like Compounds as SIRT1 Activators. Int. J. Mol. Sci. 2022, 23, 15105.
  4. Santini, S.; Cordone, V.; Mijit, M.; Bignotti, V.; Aimola, P.; Dolo, V.; Falone, S.; Amicarelli, F. SIRT1-Dependent Upregulation of Antiglycative Defense in HUVECs Is Essential for Resveratrol Protection against High Glucose Stress. Antioxidants 2019, 8, 346.
  5. Guzmán, L.; Balada, C.; Flores, G.; Álvarez, R.; Knox, M.; Vinet, R.; Martínez, J.L. T-Resveratrol Protects against Acute High Glucose Damage in Endothelial Cells. Plant Foods Hum. Nutr. 2018, 73, 235–240.
  6. Xia, N.; Forstermann, U.; Li, H. Resveratrol as a Gene Regulator in the Vasculature. Curr. Pharm. Biotechnol. 2014, 15, 401–408.
  7. DiNatale, J.C.; Crowe-White, K.M. Effects of Resveratrol Supplementation on Nitric Oxide-Mediated Vascular Outcomes in Hypertension: A Systematic Review. Nitric Oxide-Biol. Chem. 2022, 129, 74–81.
  8. Torregrosa-Muñumer, R.; Vara, E.; Fernández-Tresguerres, J.Á.; Gredilla, R. Resveratrol Supplementation at Old Age Reverts Changes Associated with Aging in Inflammatory, Oxidative and Apoptotic Markers in Rat Heart. Eur. J. Nutr. 2021, 60, 2683–2693.
  9. Reda, D.; Elshopakey, G.E.; Mahgoub, H.A.; Risha, E.F.; Khan, A.A.; Rajab, B.S.; El-Boshy, M.E.; Abdelhamid, F.M. Effects of Resveratrol Against Induced Metabolic Syndrome in Rats: Role of Oxidative Stress, Inflammation, and Insulin Resistance. Evid.-Based Complement. Altern. Med. 2022, 2022, 3362005.
  10. Rouse, M.; Younès, A.; Egan, J.M. Resveratrol and Curcumin Enhance Pancreatic β-Cell Function by Inhibiting Phosphodiesterase Activity. J. Endocrinol. 2014, 223, 107–117.
  11. Darwish, M.A.; Abdel-Bakky, M.S.; Messiha, B.A.S.; Abo-Saif, A.A.; Abo-Youssef, A.M. Resveratrol Mitigates Pancreatic TF Activation and Autophagy-Mediated Beta Cell Death via Inhibition of CXCL16/Ox-LDL Pathway: A Novel Protective Mechanism against Type 1 Diabetes Mellitus in Mice. Eur. J. Pharmacol. 2021, 901, 174059.
  12. Cui, H.; Yang, Y.; Li, X.; Zong, W.; Li, Q. Resveratrol Regulates Paracrine Function of Cardiac Microvascular Endothelial Cells under Hypoxia/Reoxygenation Condition. Pharmazie 2022, 77, 179–185.
  13. Chen, J.; Liu, Y.; Liu, Y.; Peng, J. Resveratrol Protects against Ox-LDL-Induced Endothelial Dysfunction in Atherosclerosis via Depending on Circ_0091822/MiR-106b-5p-Mediated Upregulation of TLR4. Immunopharmacol. Immunotoxicol. 2022, 44, 915–924.
  14. Liu, X.; Zhao, H.; Jin, Q.; You, W.; Cheng, H.; Liu, Y.; Song, E.; Liu, G.; Tan, X.; Zhang, X.; et al. Resveratrol Induces Apoptosis and Inhibits Adipogenesis by Stimulating the SIRT1-AMPKα-FOXO1 Signalling Pathway in Bovine Intramuscular Adipocytes. Mol. Cell. Biochem. 2018, 439, 213–223.
  15. Sun, W.; Yu, S.; Han, H.; Yuan, Q.; Chen, J.; Xu, G. Resveratrol Inhibits Human Visceral Preadipocyte Proliferation and Differentiation In Vitro. Lipids 2019, 54, 679–686.
  16. Ye, G.; Gao, H.; Wang, Z.; Lin, Y.; Liao, X.; Zhang, H.; Chi, Y.; Zhu, H.; Dong, S. PPARα and PPARγ Activation Attenuates Total Free Fatty Acid and Triglyceride Accumulation in Macrophages via the Inhibition of Fatp1 Expression. Cell Death Dis. 2019, 10, 39.
  17. Hou, X.; Xu, S.; Maitland-Toolan, K.A.; Sato, K.; Jiang, B.; Ido, Y.; Lan, F.; Walsh, K.; Wierzbicki, M.; Verbeuren, T.J.; et al. SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-Activated Protein Kinase. J. Biol. Chem. 2008, 283, 20015–20026.
  18. Fernandez-Quintela, A.; Macarulla, M.T.; Gómez-Zorita, S.; González, M.; Milton-Laskibar, I.; Portillo, M.P. Relationship between Changes in Microbiota Induced by Resveratrol and Its Anti-Diabetic Effect on Type 2 Diabetes. Front. Nutr. 2022, 9, 1084702.
  19. Zeraattalab-Motlagh, S.; Jayedi, A.; Shab-Bidar, S. The Effects of Resveratrol Supplementation in Patients with Type 2 Diabetes, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials. Am. J. Clin. Nutr. 2021, 114, 1675–1685.
  20. Liang, A.; Zhang, W.; Wang, Q.; Huang, L.; Zhang, J.; Ma, D.; Liu, K.; Li, S.; Chen, X.; Li, S.; et al. Resveratrol Regulates Insulin Resistance to Improve the Glycolytic Pathway by Activating SIRT2 in PCOS Granulosa Cells. Front. Nutr. 2023, 9, 1019562.
  21. Cao, X.; Liao, W.; Xia, H.; Wang, S.; Sun, G. The Effect of Resveratrol on Blood Lipid Profile: A Dose-Response Meta-Analysis of Randomized Controlled Trials. Nutrients 2022, 14, 3755.
  22. Zhou, Q.; Wang, Y.; Han, X.; Fu, S.; Zhu, C.; Chen, Q. Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review. Front. Physiol. 2022, 13, 480.
  23. Mohammadipoor, N.; Shafiee, F.; Rostami, A.; Kahrizi, M.S.; Soleimanpour, H.; Ghodsi, M.; Ansari, M.J.; Bokov, D.O.; Jannat, B.; Mosharkesh, E.; et al. Resveratrol Supplementation Efficiently Improves Endothelial Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Phytother. Res. 2022, 36, 3529–3539.
  24. de Ligt, M.; Bruls, Y.M.H.; Hansen, J.; Habets, M.F.; Havekes, B.; Nascimento, E.B.M.; Moonen-Kornips, E.; Schaart, G.; Schrauwen-Hinderling, V.B.; van Marken Lichtenbelt, W.; et al. Resveratrol Improves Ex Vivo Mitochondrial Function but Does Not Affect Insulin Sensitivity or Brown Adipose Tissue in First Degree Relatives of Patients with Type 2 Diabetes. Mol. Metab. 2018, 12, 39–47.
  25. Liu, K.; Zhou, R.; Wang, B.; Mi, M.T. Effect of Resveratrol on Glucose Control and Insulin Sensitivity: A Meta-Analysis of 11 Randomized Controlled Trials. Am. J. Clin. Nutr. 2014, 99, 1510–1519.
  26. Rabbani, N.; Xue, M.; Weickert, M.O.; Thornalley, P.J. Reversal of Insulin Resistance in Overweight and Obese Subjects by Trans-Resveratrol and Hesperetin Combination—Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation. Nutrients 2021, 13, 2374.
  27. Fatima, S.; Khan, D.A.; Aamir, M.; Pervez, M.A.; Fatima, F. δ-Tocotrienol in Combination with Resveratrol Improves the Cardiometabolic Risk Factors and Biomarkers in Patients with Metabolic Syndrome: A Randomized Controlled Trial. Metab. Syndr. Relat. Disord. 2023, 21, 25–34.
  28. Luca, P.; Thomas, Z.; Atkinson, R.L.; Fulvio, N.; Franco, A.; Paolo, C.; Giorgio, P.; Angelo, P. Supportive Treatment of Vascular Dysfunction in Pediatric Subjects with Obesity: The OBELIX Study. Nutr. Diabetes 2022, 12, 1329–1343.
  29. Raimundo, A.F.; Félix, F.; Andrade, R.; García-Conesa, M.T.; González-Sarrías, A.; Gilsa-Lopes, J.; do Dulce, Ó.; Raimundo, A.; Ribeiro, R.; Rodriguez-Mateos, A.; et al. Combined Effect of Interventions with Pure or Enriched Mixtures of (Poly)Phenols and Anti-Diabetic Medication in Type 2 Diabetes Management: A Meta-Analysis of Randomized Controlled Human Trials. Eur. J. Nutr. 2020, 59, 1329–1343.
  30. Li, C.; Wang, Z.; Lei, H.; Zhang, D. Recent Progress in Nanotechnology-Based Drug Carriers for Resveratrol Delivery. Drug Deliv. 2023, 30, 2174206.
  31. Barber, T.M.; Kabisch, S.; Randeva, H.S.; Pfeiffer, A.F.H.; Weickert, M.O. Implications of Resveratrol in Obesity and Insulin Resistance: A State-of-the-Art Review. Nutrients 2022, 14, 2870.
  32. Fraiz, G.M.; da Conceição, A.R.; de Souza Vilela, D.L.; Rocha, D.M.U.P.; Bressan, J.; Hermsdorff, H.H.M. Can Resveratrol Modulate Sirtuins in Obesity and Related Diseases? A Systematic Review of Randomized Controlled Trials. Eur. J. Nutr. 2021, 60, 2961–2977.
  33. Ashrafizadeh, M.; Taeb, S.; Haghi-Aminjan, H.; Afrashi, S.; Moloudi, K.; Musa, A.E.; Najafi, M.; Farhood, B. Resveratrol as an Enhancer of Apoptosis in Cancer: A Mechanistic Review. Anti-Cancer Agents Med. Chem. 2020, 21, 2327–2336.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback