Jornal Vascular Brasileiro
Jornal Vascular Brasileiro
Original Article

Inflammatory markers, endothelial function and cardiovascular risk

Marcadores inflamatórios, função endotelial e riscos cardiovasculares

Bruno Costa Teixeira; André Luiz Lopes; Rodrigo Cauduro Oliveira Macedo; Cleiton Silva Correa; Thiago Rozales Ramis; Jerri Luiz Ribeiro; Alvaro Reischak-Oliveira

Downloads: 1
Views: 224


The need to study cardiovascular diseases (CVD) has become more and more relevant as their prevalence has increased over the years. An intact endothelial wall is essential to vascular health. Certain factors are responsible for maintaining this tissue intact, including nitric oxide (NO), which provokes dilation of blood vessels in response to shear stress. Expression of the endothelial nitric oxide synthase (eNOS) enzyme, which produces nitric oxide in response to increases in blood flow, is of fundamental importance to maintenance of the vascular system. When this enzyme is inhibited, nitric oxide production is reduced, causing endothelial dysfunction. Since C-reactive protein inhibits production of nitric oxide by the eNOS enzyme, it is one of the causes of endothelial dysfunction and cardiovascular events. The objective of the present study was to review scientific articles in the literature related to the subject 'inflammatory markers and endothelial function'. A wide-ranging review of the current literature was conducted, using systematic analysis of bibliographic references indexed in PubMed, Scielo, Medline and LILACS database, for the years 1992 to 2013. The studies reviewed show that increases in inflammation causes reductions in NO and increases in cardiovascular events. Increased inflammation is associated with higher incidence of cardiovascular diseases.


inflammation, nitric oxide, endothelium


A necessidade de estudo das Doenças Cardiovasculares (DCV) vem à tona pelo aumento da sua prevalência ao longo dos anos. Uma parede endotelial íntegra é essencial para a saúde vascular. Alguns fatores são responsáveis pela integridade deste tecido, como o óxido nítrico (NO), que provoca a dilatação do vaso sanguíneo em resposta ao estresse de cisalhamento. A expressão da enzima óxido nítrico sintase endotelial (eNOS), que produz óxido nítrico em resposta ao incremento do fluxo sanguíneo, é fundamental para a manutenção do sistema vascular. Quando há inibição desta enzima, ocorre diminuição da produção de óxido nítrico, causando disfunção endotelial. A PCR inibe a produção de óxido nítrico pela enzima eNOS, sendo então uma causadora de disfunção endotelial e eventos cardiovasculares. O presente artigo tem como objetivo revisar artigos científicos na literatura relacionados ao tema 'marcadores inflamatórios e função endotelial'. Foi realizada uma ampla revisão de literatura atual, utilizando-se análise sistemática das referências bibliográficas nas bases de dados PubMed, Scielo, Medline e Lilacs, no período de 1992 a 2013. Os estudos revisados mostram que o aumento da inflamação causa uma diminuição de NO e aumento de eventos cardiovasculares. O aumento da inflamação está associado ao aumento da incidência de doenças cardiovasculares.


inflamação, óxido nítrico, endotélio


Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.

Schmidt MI, Duncan BB, Azevedo e Silva G, Menezes AM, Monteiro CA, Barreto SM. Chronic non-communicable diseases in Brazil: burden and current challenges. Lancet. 2011;377:1949-61.

Barbato JE, Tzeng E. Nitric oxide and arterial disease. J Vasc Surg. 2004;40:187-93.

Leung FP, Yung LM, Laher I, Yao X, Chen ZY, Huang Y. Exercise, vascular wall and cardiovascular diseases: an update (Part 1). Sports Med. 2008;38:1009-24.

Machado BH, Bonagamba LG. Microinjection of S-nitrosocysteine into the nucleus tractus solitarii of conscious rats decreases arterial pressure but L-glutamate does not. Eur J Pharmacol. 1992;221:179-82.

Luscher TF, Seo BG, Buhler FR. Potential role of endothelin in hypertension. Controversy on endothelin in hypertension. Hypertension. 1993;21:752-7.

Reinhardt RR, Bondy CA. Differential cellular pattern of gene expression for two distinct cGMP-inhibited cyclic nucleotide phosphodiesterases in developing and mature rat brain. Neuroscience. 1996;72:567-78.

Verma S, Devaraj S, Jialal I. Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation. 2006;113:2135-50.

Szmitko PE, Wang CH, Weisel RD, De Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation: Part I. Circulation. 2003;108:1917-23.

Tonet AC, Karnikowski M, Moraes CF. Association between the -174 G/C promoter polymorphism of the interleukin-6 gene and cardiovascular disease risk factors in Brazilian older women. Braz J Med Biol Res. 2008;41:47-53.

Ramos AM, Pellanda LC, Gus I, Portal VL. Inflammatory markers of cardiovascular disease in the elderly. Arq Bras Cardiol. 2009;92:221-8.

Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-43.

Westfelt UN, Benthin G, Lundin S, Stenqvist O, Wennmalm A. Conversion of inhaled nitric oxide to nitrate in man. Br J Pharmacol. 1995;114:1621-4.

Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-6.

Hein TW, Singh U, Vasquez-Vivar J, Devaraj S, Kuo L, Jialal I. Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis. 2009;206:61-8.

Thijssen DH, Black MA, Pyke KE. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300:H2-12.

Nathan C, Xie QW. Regulation of biosynthesis of nitric oxide. J Biol Chem. 1994;269:13725-8.

Wilcox JN, Subramanian RR, Sundell CL. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol. 1997;17:2479-88.

Vasquez-Vivar J, Kalyanaraman B, Martasek P. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998;95:9220-5.

Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003;278:22546-54.

Verma S, Wang CH, Li SH. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002;106:913-9.

Schwedler SB, Kuhlencordt PJ, Ponnuswamy PP. Native C-reactive protein induces endothelial dysfunction in ApoE-/- mice: implications for iNOS and reactive oxygen species. Atherosclerosis. 2007;195:e76-84.

Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation. 2000;102:1000-6.

Sinisalo J, Paronen J, Mattila KJ. Relation of inflammation to vascular function in patients with coronary heart disease. Atherosclerosis. 2000;149:403-11.

Tan KC, Chow WS, Tam SC, Ai VH, Lam CH, Lam KS. Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2002;87:563-8.

Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003;108:2093-8.

De Haro Miralles J, Martinez-Aguilar E, Florez A, Varela C, Bleda S, Acin F. Nitric oxide: link between endothelial dysfunction and inflammation in patients with peripheral arterial disease of the lower limbs. Interact Cardiovasc Thorac Surg. 2009;9:107-12.

Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Markers of inflammation are strong predictors of subclinical and clinical atherosclerosis in women with hypertension. Coron Artery Dis. 2009;20:15-20.

Antoniades C, Demosthenous M, Tousoulis D. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis. Hypertension. 2011;58:93-8.

Leinonen E, Hurt-Camejo E, Wiklund O, Hultén LM, Hiukka A, Taskinen MR. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis. 2003;166(2):387-94.

Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011;11:607-15.

Brevetti G, De Caterina M, Martone VD. Exercise increases soluble adhesion molecules ICAM-1 and VCAM-1 in patients with intermittent claudication. Clin Hemorheol Microcirc. 2001;24:193-9.

Souza JR, Oliveira RT, Blotta MH, Coelho OR. Níveis séricos de interleucina-6 (IL-6), interleucina-18 (IL-18) e proteína-C reativa (PCR) na síndrome coronariana aguda sem supradesnivelamento do ST em pacientes com diabete tipo 2. Arq Bras Cardiol. 2008;90:94-9.

Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245-70.

Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA. 2001;286:2107-13.

Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. The JUPITER trial results boost the evidence for the use of hsCRP as a treatment target and as part of the assessment of vascular risk: time for new guidelines?. Hellenic J Cardiol. 2009;50:89-91.

Gomez M, Valle V, Aros F. Oxidized LDL, lipoprotein (a) and other emergent risk factors in acute myocardial infarction (FORTIAM study). Rev Esp Cardiol. 2009;62:373-82.

Huelmos A, Jimenez J, Guijarro C. Underrecognized peripheral arterial disease in patients with acute coronary syndrome: prevalence of traditional and emergent cardiovascular risk factors. Rev Esp Cardiol. 2005;58:1403-10.

Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-9.

Steffel J, Luscher TF. Predicting the development of atherosclerosis. Circulation. 2009;119:919-21.

Fantuzzi G, Reed DA, Dinarello CA. IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor. J Clin Invest. 1999;104:761-7.

Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767-72.

Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation. 2003;107:398-404.

Singh U, Devaraj S, Jialal I. C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells: evidence that C-reactive protein is a procoagulant. Arterioscler Thromb Vasc Biol. 2005;25:2216-21.

5ddd84490e8825d0451da3e9 jvb Articles

J Vasc Bras

Share this page
Page Sections