Portal de Periódicos da CAPES

C-Reactive Protein Beyond Biomarker of Inflammation in Metabolic Syndrome

2011; Lippincott Williams & Wilkins; Volume: 57; Issue: 4 Linguagem: Inglês

10.1161/hypertensionaha.110.165845

1524-4563

Masatsugu Horiuchi, Masaki Mogi,

Apelin-related biomedical research

HomeHypertensionVol. 57, No. 4C-Reactive Protein Beyond Biomarker of Inflammation in Metabolic Syndrome Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBC-Reactive Protein Beyond Biomarker of Inflammation in Metabolic Syndrome Masatsugu Horiuchi and Masaki Mogi Masatsugu HoriuchiMasatsugu Horiuchi From the Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan. and Masaki MogiMasaki Mogi From the Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan. Originally published28 Feb 2011https://doi.org/10.1161/HYPERTENSIONAHA.110.165845Hypertension. 2011;57:672–673Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 See related article, pp 731–737The metabolic syndrome is characterized by low-grade inflammation. C-reactive protein (CRP), the best characterized biomarker of inflammation, is an independent predictor of future cardiovascular events, and elevated CRP level has also been implicated in the development of type 2 diabetes mellitus, a strong risk factor for cardiovascular disease. Recent reports have provided provocative evidence that high-sensitive CRP may impair insulin signaling.1 Accumulating evidence suggests a close association of CRP and the pathogenesis of metabolic syndrome. Therefore, it has been also proposed that high-sensitive CRP should be added as a clinical criterion for metabolic syndrome and for creation of a high-sensitive CRP-modified coronary heart disease risk score.2 However, it is still an enigma whether the increase in CRP contributes to the pathogenesis of metabolic syndrome, per se, or is a secondary response to inflammation in this disease state.In this regard, Pravenec et al3 demonstrated increases in blood pressure, insulin resistance, microalbuminuria, and plasma triglyceride and reduced serum adiponectin in spontaneously hypertensive rats (SHRs) in which human CRP was transgenically expressed in the liver under control of the apolipoprotein E promoter. This transgenic rat showed enhanced inflammation and oxidative stress. As commented by the authors,3 one of the next important issues to be addressed is whether their observation is specific for this hypertensive model or not, because their studies on the metabolic effects of human CRP were performed in the SHR model, which is a strain known to be genetically susceptible to developing multiple features of the metabolic syndrome. Therefore, we speculate that other hypertensive models or strains might differ from SHRs in terms of the effect of CRP on the pathogenesis of metabolic syndrome. This kind of analysis is crucial, especially in terms of investigating the actual roles of CRP in the pathogenesis of metabolic disorders with elevated blood pressure. It would also be intriguing to address whether the possible increase in blood pressure by CRP induces multiple or specific features of metabolic syndrome and/or whether some CRP-mediated specific features of metabolic disorders, such as insulin resistance, act as a trigger for the increase in blood pressure (Figure). Moreover, it has to be clarified whether the state of high blood pressure is mandatory for the possible CRP-mediated pathogenesis of metabolic disorders, such as insulin resistance and adipocytokine dysregulation.Download figureDownload PowerPointFigure. Possible roles of CRP in pathogenesis of metabolic syndrome and cardiovascular disorders.It is reported that chronic elevation of CRP is associated with a greater risk of hypertension, and Vongpatanasin et al4 reported that CRP transgenic mice showed an exaggerated blood pressure elevation in response to angiotensin II and a reduction in vascular angiotensin receptor subtype 2 expression with no change in angiotensin receptor subtype 1 and that the response to angiotensin II was reversed by an NO donor, which indicates a role for NO deficiency in the process. Schwartz et al5 reported that CRP downregulates endothelial NO synthase and attenuates reendothelialization in vivo in mice, and this action of CRP on endothelial NO synthase is mediated at the level of gene transcription. Angiotensin receptor subtype 2 receptor stimulation is also known to enhance the bradykinin/NO system in various organs including the vasculature,6 suggesting that CRP could cross-link the angiotensin receptor subtype 2 receptor with NO production, thereby regulating blood pressure (Figure).In contrast, Kusche-Vihrog et al7 demonstrated recently that inhibition of the release of NO did not have an effect on CRP-induced stiffening of endothelial cells and that CRP enhanced the effects of aldosterone on the mechanical properties of the endothelium. Moreover, Zhang et al8 investigated the functional importance of human CRP in hypertensive cardiac remodeling by chronic infusion of angiotensin II into mice expressing human CRP and demonstrated that CRP promotes cardiac fibrosis and inflammation under high angiotensin II conditions, with enhanced upregulation of the angiotensin receptor subtype 1 and activation of the transforming growth factor-β/Smad and nuclear factor-κB signaling pathways. Taken together, these results suggest that possible cross-talk of the renin-angiotensin system and CRP plays a role in cardiovascular remodeling.Pravenec et al3 also reported that transgenic CRP promotes insulin resistance in the SHR. The in vitro study by D'Alessandris et al9 suggested that human recombinant CRP may cause insulin resistance by increasing insulin receptor substrate 1 phosphorylation at Ser (307) and Ser (612) via c-Jun N-terminal kinase and extracellular signal–regulated kinase 1/2, respectively, leading to impaired insulin-stimulated glucose uptake, glucose transporter type 4 translocation, and glycogen synthesis mediated by insulin receptor substrate 1/phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3. Insulin resistance is well known to be closely associated with an increase in blood pressure, implying that the CRP-mediated blood pressure increase could be at least in part attributed to CRP-mediated insulin resistance (Figure). The metabolic syndrome is typically characterized by obesity associated with hypertension, hyperlipidemia, and hyperglycemia, and dysregulated adipose tissue functions appear to be important factors in exaggeration of the metabolic syndrome and the pathogenesis of cardiovascular disease. Furthermore, the reciprocal association of adiponectin and CRP levels in both human plasma and white adipose tissue in mice suggests that adipose tissue might participate in the development of atherosclerosis,10 and Pravenec et al3 also observed reduced serum adiponectin in SHRs in which human CRP was transgenically expressed in the liver. It is interesting to speculate that the increase in CRP in adipose tissue in patients with abdominal obesity would dysregulate adipocytokine production, which would contribute to the pathogenesis of metabolic syndrome, eventually resulting in insulin resistance and diabetes mellitus and its associated cardiovascular events (Figure). It is also possible that an increase in CRP could impair the synthesis and secretion of insulin in the pancreas because of CRP-mediated inflammation and oxidative stress, and this possibility should also be addressed.Elevated CRP is also a risk factor for the development of cardiovascular disease, irrespective of metabolic syndrome, mainly because of exaggeration of inflammation and oxidative stress. Given that CRP is a critical determinant of the exaggeration of cardiovascular disorders, including hypertension and metabolic disorders, not merely as a simple biomarker of these disease states, it is important to further examine the details of the signaling mechanism of CRP-mediated inflammation and oxidative stress and specific target organs of CRP and the localization of CRP receptors to understand the roles of CRP in the pathogenesis of metabolic syndrome and cardiovascular disease and to develop clinical interventions against CRP-mediated effects.DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Masatsugu Horiuchi, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail [email protected]ehime-u.ac.jpReferences1. Devaraj S, Singh U, Jialal I. Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol. 2009; 20:182–189.CrossrefMedlineGoogle Scholar2. Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk?Circulation. 2004; 109:2818–2825.LinkGoogle Scholar3. Pravenec M, Kajiya T, Zídek V, Landa V, Mlejnek P, Šimáková M, Šilhavý J, Malínská H, Oliyarnyk O, Kazdová L, Fan J, Wang J, Kurtz TW. Effects of human C-reactive protein on pathogenesis of features of the metabolic syndrome. Hypertension. 2011; 57:731–737.LinkGoogle Scholar4. Vongpatanasin W, Thomas GD, Schwartz R, Cassis LA, Osborne-Lawrence S, Hahner L, Gibson LL, Black S, Samols D, Shaul PW. C-reactive protein causes downregulation of vascular angiotensin subtype 2 receptors and systolic hypertension in mice. Circulation. 2007; 115:1020–1028.LinkGoogle Scholar5. Schwartz R, Osborne-Lawrence S, Hahner L, Gibson LL, Gormley AK, Vongpatanasin W, Zhu W, Word RA, Seetharam D, Black S, Samols D, Mineo C, Shaul PW. C-reactive protein downregulates endothelial NO synthase and attenuates reendothelialization in vivo in mice. Circ Res. 2007; 100:1405–1407.LinkGoogle Scholar6. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T, for the International Union of Pharmacology, XXIII. The angiotensin II receptors. Pharmacol Rev. 2000; 52:415–472.MedlineGoogle Scholar7. Kusche-Vihrog K, Urbanova K, Blanqué A, Wilhelmi M, Schillers H, Kliche K, Pavenstädt H, Brand E, Oberleithner H. C-reactive protein makes human endothelium stiff and tight. Hypertension. 2010; 57:231–237.LinkGoogle Scholar8. Zhang R, Zhang YY, Huang XR, Wu Y, Chung AC, Wu EX, Szalai AJ, Wong BC, Lau CP, Lan HY. C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease. Hypertension. 2010; 55:953–960.LinkGoogle Scholar9. D'Alessandris C, Lauro R, Presta I, Sesti G. C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser 612 in L6 myocytes, thereby impairing the insulin signaling pathway that promotes glucose transport in L6 myotubes. Diabetologia. 2007; 50:840–849.CrossrefMedlineGoogle Scholar10. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation. 2003; 107:671–674.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Weng G, Shen X, Li J, Wang J, Zhu J and Zhao J (2022) A plasmonic ELISA for multi-colorimetric sensing of C-reactive protein by using shell dependent etching of Ag coated Au nanobipyramids, Analytica Chimica Acta, 10.1016/j.aca.2022.340129, 1221, (340129), Online publication date: 1-Aug-2022. Börnhorst C, Russo P, Veidebaum T, Tornaritis M, Molnár D, Lissner L, Mårild S, De Henauw S, Moreno L, Floegel A, Ahrens W and Wolters M (2020) The role of lifestyle and non-modifiable risk factors in the development of metabolic disturbances from childhood to adolescence, International Journal of Obesity, 10.1038/s41366-020-00671-8, 44:11, (2236-2245), Online publication date: 1-Nov-2020. Kaltenecker D, Themanns M, Mueller K, Spirk K, Suske T, Merkel O, Kenner L, Luís A, Kozlov A, Haybaeck J, Müller M, Han X and Moriggl R (2019) Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression, Cytokine, 10.1016/j.cyto.2018.10.010, 124, (154569), Online publication date: 1-Dec-2019. Yu J, Ho C, Wang H, Chen Y and Hsieh C (2017) Acupuncture on Renal Function in Patients with Chronic Kidney Disease: A Single-Blinded, Randomized, Preliminary Controlled Study, The Journal of Alternative and Complementary Medicine, 10.1089/acm.2016.0119, 23:8, (624-631), Online publication date: 1-Aug-2017. Abdelkarem H and Fadda L (2017) Flaxseed and quercetin improve anti-inflammatory cytokine level and insulin sensitivity in animal model of metabolic syndrome, the fructose-fed rats, Arabian Journal of Chemistry, 10.1016/j.arabjc.2013.11.042, 10, (S3015-S3020), Online publication date: 1-May-2017. Rabadán-Chávez G, Reyes-Maldonado E, Quevedo-Corona L, Paniagua-Castro N, Escalona-Cardoso G and Jaramillo-Flores M (2016) The prothrombotic state associated with obesity-induced hypertension is reduced by cocoa and its main flavanols, Food & Function, 10.1039/C6FO01165A, 7:12, (4880-4888) Li J, Flammer A, Lennon R, Nelson R, Gulati R, Friedman P, Thomas R, Sandhu N, Hua Q, Lerman L and Lerman A (2012) Comparison of the Effect of the Metabolic Syndrome and Multiple Traditional Cardiovascular Risk Factors on Vascular Function, Mayo Clinic Proceedings, 10.1016/j.mayocp.2012.07.004, 87:10, (968-975), Online publication date: 1-Oct-2012. April 2011Vol 57, Issue 4 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.110.165845PMID: 21357270 Originally publishedFebruary 28, 2011 PDF download Advertisement SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemAnimal Models of Human DiseaseEpidemiologyMetabolismObesity