Anti-Inflammatory Effects of Atorvastatin Therapy in Metabolic Syndrome

Metabolic Syndrome; Obesity, Abdominal; Diabetes Mellitus; Hypertension; Endothelium/etiology; Inflammation; Atorvastatin/drug therapy

Metabolic Syndrome (MS) is a condition characterized by abdominal obesity accompanied by high fasting glucose levels, insulin resistance, arterial hypertension, and dyslipidemia.¹ It configures a critical risk factor for developing other clinical conditions, primarily type 2 diabetes mellitus (DM2) and cardiovascular diseases.¹ , ² Also, MS has been associated with endothelial dysfunction, characterized by changes in arterial vascular architecture, especially in the endothelium and capillary basement membrane, causing microvascular complications. Endothelial basement membrane remodeling commonly includes erosion and vascular thrombosis processes in individuals with MS.²

Endothelial dysfunction pathogenesis is a multifactorial event and may include chronic inflammation resulting from leukocytes activation and increased production of reactive oxygen species, which are commonly associated with MS.³ The pro-inflammatory phenotype related to MS makes the vasculature highly vulnerable to tumor necrosis factor-alpha (TNF-α), C-reactive protein, interleukin-6 (IL-6), and interleukin-8 (IL-8)-induced inflammatory processes.⁴ , ⁵ High levels of these pro-inflammatory markers are commonly associated with MS.⁵ - ⁷ Likewise, low-density lipoproteins (LDL) oxidation resulting from lipid peroxidation has immunogenic and pro-inflammatory effects, based on the recruitment and accumulation of pro-inflammatory cells.⁵ These effects may sustain endothelial dysfunction that is associated with smooth muscle cell proliferation and perivascular adipose tissue hypertrophy, events commonly observed during the endothelial remodeling process.⁸

Classically, ectopic fat deposition around visceral vessels and organs has contributed to low-grade chronic inflammatory conditions and insulin resistance onset, which is also common in obesity.⁹ , ¹⁰ In this aspect, perivascular adipose tissue has an essential paracrine function sustained by substantial protein activation and vascular morphological changes; these mechanisms contribute to the endothelial dysfunction during MS.⁸ , ¹¹ Consequently, clarifying the potential efficiency of therapeutic interventions is essential to manage MS conditions. In this context, hydroxymethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA), also called statins, are commonly used to treat atherosclerotic cardiovascular disease, and have proved efficacy in normalizing serum cholesterol levels.¹² Indeed, atorvastatin is currently one of the most used statins in the clinical context as it has a long plasma half-life and presents significant tolerability and safety.¹³

In the current edition of the Arquivos Brasileiros de Cardiologia, Carvalho et al.¹⁴ documented beneficial effects of atorvastatin intervention on nutritional, metabolic and vascular aspects in an experimental model of hyperglycemic diet-induced metabolic syndrome. As expected, hyperglycidic diet-induced MS was accompanied by several disorders, as increased body mass and adiposity, high levels of total cholesterol, low (LDL) and very low (VLDL) densities hypertriglyceridemia, hyperglycemia, and reduced high-density lipoprotein (HDL) levels. Moreover, the dietary intervention promoted inflammatory effects, sustained by an increase in systemic and tissue levels of TNF-α and IL-6, perivascular adipose tissue hypertrophy and vascular changes.¹⁴ In response to atorvastatin, findings included a reduction in body mass and adiposity measures and decreased LDL, VLDL, triglycerides, as well as increased HDL levels. In the morphological context, atorvastatin reduced the transverse sectional area and the thickness of the vessel’s media layer and reduced the size and number of perivascular adipocytes. Another substantial atorvastatin effect included the reduction of TNF-α and IL-6 levels into MS, suggesting that these cytokines modulate the endothelial remodeling process.¹⁵

Therefore, the results of this study show that atorvastatin interventions may be effective as a medical intervention for preventive strategy and treatment of vascular conditions associated with MS. However, further studies are needed to elucidate potential mechanisms involved with metabolic and cardiovascular disorders in MS.

Acknowledgments

Federal University of Mato Grosso do Sul – UFMS/MEC – Brasil; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) - Código de Financiamento 001, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT).

Referências

• ¹
  Lima TR, Silva DAS, Giehl MWC, D’Orsi E, González-Chica DA. Clusters of Cardiometabolic Risk Factors and Their Association with Atherosclerosis and Chronic Inflammation among Adults and Elderly in Florianópolis, Southern Brazil. Arq Bras Cardiol. 2021; 117(1):39-48. doi: 10.36660/abc.20200230.
• ²
  Tran V, De Silva TM, Sobey CG, Lim K, Drummond GR, Vinh A, Jelinic M. The Vascular Consequences of Metabolic Syndrome: Rodent Models, Endothelial Dysfunction, and Current Therapies. Front Pharmacol. 2020;11:148.doi: 10.3389/fphar.2020.00148.
  » https://doi.org/10.3389/fphar.2020.00148.
• ³
  Varghese JF, Patel R, Yadav UCS. Novel Insights in the Metabolic Syndrome-induced Oxidative Stress and Inflammation-mediated Atherosclerosis. Curr Cardiol Rev. 2018; 14;14(1):4-14. doi: 10.2174/1573403X13666171009112250.
• ⁴
  Faria AP, Ritter AMV, Gasparetti CS, Corrêa NB, Brunelli V, Almeida A, et al. A Proposed Inflammatory Score of Circulating Cytokines/Adipokines Associated with Resistant Hypertension, but Dependent on Obesity Parameters. Arq Bras Cardiol. 2019;112(4):383-9. doi: 10.5935/abc.20190032.
• ⁵
  Francisco G, Hernández C, Simó R. Serum markers of vascular inflammation in dyslipemia. Clin Chim Acta. 2006;369(1):1-16. doi: 10.1016/j.cca.2005.12.027.
• ⁶
  Sharafi SM, Mahdavi M, Riahi R, Kheirollahi M, Kelishadi R. Meta-Analysis on the Association of C-Reactive Protein Polymorphisms with Metabolic Syndrome. Glob Med Genet. 2020;7(1):8-13. doi: 10.1055/s-0040-1710548.
• ⁷
  Jarecki P, Herman WA, Losy J, Lacka K. The Comparison of Predictive Value Among Chemerin, IL-18 and Hormonal Parameters in Assessing the Risk of Metabolic Syndrome in Men. Am J Mens Health. 2021;15(4):15579883211034984. doi: 10.1177/1557988321103498.
• ⁸
  Xia N, Li H. The role of perivascular adipose tissue in obesity-induced vascular dysfunction. Br J Pharmacol. 2017; 174(20):3425-42. doi: 10.1111/bph.13650.
  » https://doi.org/10.1111/bph.13650
• ⁹
  Martins F, Campos DH, Pagan LU, Martinez PF, Okoshi K, Okoshi MP, et al.. High-fat Diet Promotes Cardiac Remodeling in an Experimental Model of Obesity. Arq Bras Cardiol. 2015;105(5):479-86. doi: 10.5935/abc.20150095.
• ¹⁰
  Oliveira-Junior SA, Muzili N, Carvalho MR, Ota GE, Morais CS, Vieira LFC, et al. AT1 Receptor Blockade Improves Myocardial Functional Performance in Obesity. Arq Bras Cardiol. 2020;115(1):17-28. doi: 10.36660/abc.20190131.
• ¹¹
  Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S, Coutinho P, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013; 4;127(22):2209-21. doi: 10.1161/CIRCULATIONAHA.112.001133
• ¹²
  Toth PP, Banach M. Statins: Then and Now. Methodist Debakey Cardiovasc J. 2019;15(1):23-31. doi: 10.14797/mdcj-15-1-23.
• ¹³
  Moon J, Yoo S, Koh G, Min KW, Shin HH. Efficacy and Safety of High-Dose Atorvastatin in Moderate-to-High Cardiovascular Risk Postmenopausal Korean Women with Dyslipidemia. J Lipid Atheroscler. 2020;9(1):162-71. doi: 10.12997/jla.2020.9.1.162.
• ¹⁴
  Carvalho KFS, Ferreira AAM, Barbosa NC, Alves JV, Costa RM. Atorvastatin Attenuates Vascular Remodeling in Mice with Metabolic Syndrome. Arq Bras Cardiol. 2021; 117(4):737-747.
• ¹⁵
  Chu T, Huang M, Zhao Z, Ling F, Cao J, Ge J. Atorvastatin Reduces Accumulation of Vascular Smooth Muscle Cells to Inhibit Intimal Hyperplasia via p38 MAPK Pathway Inhibition in a Rat Model of Vein Graft. Arq Bras Cardiol. 2020;115(4):630-6. doi: 10.36660/abc.20190231.

• Short Editorial related to the article: Atorvastatin Attenuates Vascular Remodeling in Mice with Metabolic Syndrome

Publication Dates

• Publication in this collection
  25 Oct 2021
• Date of issue
  Oct 2021