Generic placeholder image

Current Cardiology Reviews


ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

Systematic Review Article

Dose-related Effects of Resveratrol in Different Models of Pulmonary Arterial Hypertension: A Systematic Review

Author(s): Andressa C. Ferreira, Jerdianny S. Serejo, Rafael Durans, Jadna M. Pereira Costa, Antonio W.S. Maciel, Adeilson S.M. Vieira, Carlos A. A. Dias-Filho, Carlos J. Dias, Maria R.Q. Bomfim, Cristiano T. Mostarda and Janaina de O. Brito-Monzani*

Volume 16 , Issue 3 , 2020

Page: [231 - 240] Pages: 10

DOI: 10.2174/1573403X15666191203110554

Price: $65


Background: Pulmonary Arterial Hypertension (PAH) is a severe and progressive disease of pulmonary arterioles. This pathology is characterized by elevation of the pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart failure and death. Studies have demonstrated that resveratrol possesses a protective effect on the mechanisms related to the genesis of the PAH-induced by different models.

Objective: This study aimed to investigate the dose-related effects of resveratrol in different models of pulmonary arterial hypertension.

Methods: To identify eligible papers, we performed a systematic literature search on Scielo, Pub- Med, and Scholar Google. The research was limited to articles written in English in the last 10 years. We used the following descriptors to search: Pulmonary Arterial Hypertension and Resveratrol, OR Resveratrol, and Animal models of Pulmonary Arterial Hypertension, OR Resveratrol, and in vitro models of Pulmonary Arterial Hypertension.

Results: 1724 studies were identified through the descriptors used, fifty-five studies with different models of pulmonary arterial hypertension were selected for the full review, forty-four were excluded after application of exclusion and inclusion criteria, totalizing eleven studies included in this systematic review.

Conclusion: The results showed that resveratrol, at low and high doses, protects in a dosedependent manner against the development of PAH induced through monocrotaline, normoxia and hypoxia models. In addition to having chemopreventive, anti-inflammatory, antioxidant and antiproliferative properties. In the case of PAH-related myocardial injury, resveratrol protects cells from apoptosis, thus working as an antiapoptotic agent.

Keywords: Pulmonary hypertension, resveratrol, drug therapy, administration and dosage, inflammation, oxidative stress, right ventricular failure.

Graphical Abstract
Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 2017; 50(2) 1700889
[] [PMID: 28775050]
Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004; 351(16): 1655-65.
[] [PMID: 15483284]
Jayasekera G, Crowe T, Mackenzie A, et al. Left atrial function by cardiac MRI in idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF).C106 Money don’t matter tonight: pulmonary hypertension assessment, prognostication, and treatment. Am Thorac Soc 2017; 195: A6903-3.
Hoeper MM, Galiè N. Letter by Hoeper and Galie regarding article, “Hemodynamic, functional, and clinical responses to pulmonary artery denervation in patients with pulmonary arterial hypertension of different causes: Phase II results from the pulmonary artery denervation-1 study. Circ Cardiovasc Interv 2016; 9(1) e003422
[] [PMID: 26755573]
Paffett ML, Hesterman J, Candelaria G, et al. Longitudinal in vivo SPECT/CT imaging reveals morphological changes and cardiopulmonary apoptosis in a rodent model of pulmonary arterial hypertension. PLoS One 2012; 7(7) e40910
[] [PMID: 22815866]
Meloche J, Courchesne A, Barrier M, et al. Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology. J Am Heart Assoc 2013; 2(1) e005157
[] [PMID: 23525442]
Bazavan M, Macaluso GP, Pauwaa S. Understanding cardiovascular hemodynamics.In: Desai C, Cotts WG, Lerma EV, Rudnick MR.. Ventricular-assist devices and kidney disease. Springer 2018; pp. 15-32.
Klings ES, Machado RF, Barst RJ, et al. American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease. An official American Thoracic Society clinical practice guideline: Diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med 2014; 189(6): 727-40.
[] [PMID: 24628312]
Hoette S, Jardim C, Souza Rd. Diagnosis and treatment of pulmonary hypertension: An update. J Bras Pneumol 2010; 36(6): 795-811.
[] [PMID: 21225184]
Valerio CJ, Schreiber BE, Handler CE, Denton CP, Coghlan JG. Borderline mean pulmonary artery pressure in patients with systemic sclerosis: Transpulmonary gradient predicts risk of developing pulmonary hypertension. Arthritis Rheum 2013; 65(4): 1074-84.
[] [PMID: 23280155]
Siafakas NM, Vermeire P, Pride NB, et al. The European Respiratory Society Task Force. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur Respir J 1995; 8(8): 1398-420.
[] [PMID: 7489808]
Barreto AC, Franchi SM, Pereira AC, Lopes AA. Pulmonary arterial hypertension. Physiopathology, genetic aspects and response to the chronic use of sildenafil. Arq Bras Cardiol 2005; 85(2): 147-54.
[PMID: 16113857]
Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: Results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 2012; 186(8): 790-6.
[] [PMID: 22798320]
Steendijk P. Right ventricular function and failure: Methods, models, and mechanisms. Crit Care Med 2004; 32(4): 1087-9.
[] [PMID: 15071415]
Kovacs G, Maier R, Aberer E, et al. Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma. Am J Respir Crit Care Med 2009; 180(9): 881-6.
[] [PMID: 19679693]
Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 2009; 119(11): 1518-23.
[] [PMID: 19273723]
Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: Pulmonary vascular disease: the global perspective. Chest 2010; 137(6)(Suppl.): 20S-9S.
[] [PMID: 20522577]
Opitz CF, Hoeper MM, Gibbs JSR, et al. Pre-capillary, combined, and post-capillary pulmonary hypertension: A pathophysiological continuum. J Am Coll Cardiol 2016; 68(4): 368-78.
[] [PMID: 27443433]
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62(25)(Suppl.): D34-41.
[] [PMID: 24355639]
Scalia GM, Scalia IG, Kierle R, et al. ePLAR - The echocardiographic pulmonary to left atrial ratio - A novel non-invasive parameter to differentiate pre-capillary and post-capillary pulmonary hypertension. Int J Cardiol 2016; 212: 379-86.
[] [PMID: 27061467]
McLaughlin VV, Archer SL, Badesch DB, et al. American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: A report of the American College of Cardiology Foundation Task Force on expert consensus documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009; 53(17): 1573-619.
[] [PMID: 19389575]
Chen Y, Jowett S, Barton P, et al. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: A systematic review and economic evaluation NIHR Health Technology Assessment programme: Executive Summaries. NIHR Journals Library 2009.
Zha LH, Zhou J, Li TZ, et al. NLRC3 inhibits MCT-induced pulmonary hypertension in rats via attenuating PI3K activation. J Cell Physiol 2019.
[] [PMID: 30767203]
Vendrov AE, Lozhkin A, Madamanchi NR, Runge MS. Nox4 deletion attenuates age-associated vascular inflammation and atherosclerosis burden in hyperlipidemic mice by modulating macrophage phenotype. Circulation 2018; 138(Suppl_1): A17163-3.
Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003; 22(2): 358-63.
[] [PMID: 12952274]
Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004; 109(2): 159-65.
[] [PMID: 14734504]
Ramos RP, Ferreira EVM, Arakaki JSO. Estratégias do tratamento da hipertensão arterial pulmonar. Pulmão RJ 2015; 24(2): 71-7.
Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: Evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation 1987; 76(1): 135-41.
[] [PMID: 2954725]
Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006; 151(4): 851. e1-5.
Xu D, Li Y, Zhang B, et al. Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats. Int J Med Sci 2016; 13(12): 942-54.
[] [PMID: 27994500]
Mishra V, Shuai B, Kodali M, et al. Resveratrol treatment after status epilepticus restrains neurodegeneration and abnormal neurogenesis with suppression of oxidative stress and inflammation. Sci Rep 2015; 5: 17807.
[] [PMID: 26639668]
Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol 2010; 635(1-3): 1-8.
[] [PMID: 20303945]
Rich S, Brundage BH, Levy PS. The effect of vasodilator therapy on the clinical outcome of patients with primary pulmonary hypertension. Circulation 1985; 71(6): 1191-6.
[] [PMID: 3995712]
Chan CC, Cheng LY, Lin CL, Huang YH, Lin HC, Lee FY. The protective role of natural phytoalexin resveratrol on inflammation, fibrosis and regeneration in cholestatic liver injury. Mol Nutr Food Res 2011; 55(12): 1841-9.
[] [PMID: 22086758]
Tian W, Yang L, Liu Y, et al. Resveratrol attenuates doxorubicin-induced cardiotoxicity in rats by up-regulation of vascular endothelial growth factor B. J Nutr Biochem 2019.
[] [PMID: 30857673]
Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: A review of clinical trials. NPJ precision oncology 2017; 1(1): 35.
de Sá Coutinho D, Pacheco MT, Frozza RL, Bernardi A. Anti-inflammatory effects of resveratrol: Mechanistic insights. Int J Mol Sci 2018; 19(6): 1812.
[] [PMID: 29925765]
Paffett ML, Lucas SN, Campen MJ. Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: A potential role for atrogin-1 in smooth muscle. Vascul Pharmacol 2012; 56(1-2): 64-73.
[] [PMID: 22146233]
Wilson DN, Schacht SE, Al-Nakkash L, Babu JR, Broderick TL. Resveratrol prevents pulmonary trunk remodeling but not right ventricular hypertrophy in monocrotaline-induced pulmonary hypertension. Pathophysiology 2016; 23(4): 243-50.
[] [PMID: 27374951]
Kwon Y-J, Chung T-H, Shim J-Y, Lee Y-J. The association of pulse pressure with metabolic syndrome in Korean elderly: A nationwide population-based study. Diabetes Res Clin Pract 2017; 123: 75-81.
[] [PMID: 27997862]
Shi W, Zhai C, Feng W, et al. Resveratrol inhibits monocrotaline-induced pulmonary arterial remodeling by suppression of SphK1-mediated NF-κB activation. Life Sci 2018; 210: 140-9.
[] [PMID: 30179628]
Yang DL, Zhang HG, Xu YL, et al. Resveratrol inhibits right ventricular hypertrophy induced by monocrotaline in rats. Clin Exp Pharmacol Physiol 2010; 37(2): 150-5.
[] [PMID: 19566840]
Chen B, Xue J, Meng X, Slutzky JL, Calvert AE, Chicoine LG. Resveratrol prevents hypoxia-induced arginase II expression and proliferation of human pulmonary artery smooth muscle cells via Akt-dependent signaling. Am J Physiol Lung Cell Mol Physiol 2014; 307(4): L317-25.
[] [PMID: 24951775]
Yu L, Tu Y, Jia X, et al. Resveratrol protects against pulmonary arterial hypertension in rats via activation of silent information regulator 1. Cell Physiol Biochem 2017; 42(1): 55-67.
[] [PMID: 28494457]
Florentin J, Coppin E, Vasamsetti SB, et al. Inflammatory macrophage expansion in pulmonary hypertension depends upon mobilization of blood-borne monocytes. J Immunol 2018; 200(10): 3612-25.
[] [PMID: 29632145]
Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 151(5): 1628-31.
[] [PMID: 7735624]
Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009; 104(2): 236-44, 28p following 244.
[] [PMID: 19074475]
Csiszar A, Labinskyy N, Olson S, et al. Resveratrol prevents monocrotaline-induced pulmonary hypertension in rats. Hypertension 2009; 54(3): 668-75.
[] [PMID: 19597040]
Gülçin İ. Antioxidant properties of resveratrol: A structure–activity insight. Innov Food Sci Emerg Technol 2010; 11(1): 210-8.
Mandegar M, Fung Y-CB, Huang W, Remillard CV, Rubin LJ, Yuan JX-J. Cellular and molecular mechanisms of pulmonary vascular remodeling: Role in the development of pulmonary hypertension. Microvasc Res 2004; 68(2): 75-103.
[] [PMID: 15313118]
Akagi S, Matsubara H, Nakamura K, Ito H. Modern treatment to reduce pulmonary arterial pressure in pulmonary arterial hypertension. J Cardiol 2018; 72(6): 466-72.
[] [PMID: 29898864]
Guan Z, Shen L, Liang H, et al. Resveratrol inhibits hypoxia-induced proliferation and migration of pulmonary artery vascular smooth muscle cells by inhibiting the phosphoinositide 3-kinase/protein kinase B signaling pathway. Mol Med Rep 2017; 16(2): 1653-60.
[] [PMID: 28656233]
Steven S, Oelze M, Brandt M, et al. Pentaerythritol tetranitrate in vivo treatment improves oxidative stress and vascular dysfunction by suppression of endothelin-1 signaling in monocrotaline-induced pulmonary hypertension. Oxi Med Cell Longev 2017.
Zhou S, Li M-T, Jia Y-Y, et al. Regulation of cell cycle regulators by SIRT1 contributes to resveratrol-mediated prevention of pulmonary arterial hypertension. BioMed research Int 2015; 2015 762349
Hsieh T-c, Wu JM. Unraveling and trailblazing cardioprotection by resveratrol. In: Resveratrol: State-of-the-art science and health applications-actionable targets and mechanisms of resveratrol. 2018; pp. 1-28.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy