The impact of rosuvastatin on inflammatory markers in L-NAME induced hypertensive rats
DOI:
https://doi.org/10.15218/zjms.2023.011Keywords:
Rosuvastatin, Hypertension, Inflammatory markersAbstract
Background and objective: Many clinical trials have revealed that HMG-CoA reductase inhibitors (statins) have anti-inflammatory effects through their pleiotropic activities there by decreasing the risk of cardiovascular disease (CVD). This study intended to evaluate the effect of rosuvastatin on the level of inflammatory markers (hsCRP, IL-6, sCD40L, Lp-PLA2, and cystatin C) in normotensive and hypertensive rats.
Methods: Twenty-four male Wister rats were divided into two groups of twelve. Group 1 consisted of normotensive rats, while Group 2 served as the hypertensive model. Each group was further subdivided into two groups. Subgroup A served as the control group which received the only placebo and subgroup B was the treatment arm which received rosuvastatin 10mg/kg daily for 4 weeks.
Results: Rosuvastatin did not significantly affect blood pressure and heart rate in both normotensive and hypertensive rats. The level of inflammatory markers (hsCRP, IL-6, and Lp-PLA2) significantly increased in hypertensive rats, while the level of both sCD40L and cystatin C did not change. Rosuvastatin lowered the level of IL-6, sCD40L, Lp-PLA2, and cystatin C significantly in hypertensive model rats. However, the level of hsCRP was non-significantly reduced by rosuvastatin. In normotensive rats treated with rosuvastatin, the level of cystatin C was significantly reduced.
Conclusion: Rosuvastatin significantly decreased the level of IL-6, Lp-PLA2, sCD40L, and cystatin C in hypertensive rats while in normotensive rats, rosuvastatin treatment produced only a reduction of cystatin C. Our results suggest an anti-inflammatory effect of rosuvastatin in hypertention through reduction of inflammatory markers.
Metrics
References
Wadhera RK, Steen DL, Khan I, Giugliano RP, Foody JM. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. 2016; 10(3):472–89. https://doi.org/10.1016/j.jacl.2015.11.010
Koskinas KC, Siontis GCM, Piccolo R, Mavridis D, Räber L, Mach F, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J. 2018; 39(14):1172–1180. https://doi.org/10.1093/eurheartj/ehx566
Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M. Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis. Int J Cardiol. 2010; 138(1):25–31. https://doi.org/10.1016/j.ijcard.2008.08.001
Farmer JA, Gotto AM. The Heart Protection Study: expanding the boundaries for high-risk coronary disease prevention. Am J Cardiol 2003; 92(1):3–9. https://doi.org/10.1016/s0002-9149(03)00503-4
Satoh M, Takahashi Y, Tabuchi T, Minami Y, Tamada M, Takahashi K, et al. Cellular and molecular mechanisms of statins: an update on pleiotropic effects. Clin Sci (Lond). 2015; 129(2):93–105. https://doi.org/10.1042/cs20150027
Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017; 120(1):229–43. https://doi.org/10.1161/CIRCRESAHA.116.308537
Rhee MY, Ahn T, Chang K, Chae SC, Yang TH, Shim WJ, et al. The efficacy and safety of co-administration of fimasartan and rosuvastatin to patients with hypertension and dyslipidemia. BMC Pharmacol Toxicol. 2017; 18(2). https://doi.org/10.1186/s40360-016-0112-7
De Miguel C, Rudemiller NP, Abais JM, Mattson DL. Inflammation and hypertension: new understandings and potential therapeutic targets. Curr Hypertens Rep. 2015; 17(1):507. https://doi.org/10.1007/s11906-014-0507-z
Tsounis D, Bouras G, Giannopoulos G, Papadimitriou C, Alexopoulos D, Deftereos S. Inflammation markers in essential hypertension. Med Chem. 2014; 10(7):672–81. https://doi.org/10.2174/1573406410666140318111328
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359(21):2195–207. https://doi.org/10.1016/j.jvs.2008.12.037
Wang Y, Kuang ZM, Feng SJ, Jiang L, Chen QX, Ji XY, et al. Combined antihypertensive and statin therapy for the prevention of cardiovascular events in patients with hypertension without complications: protocol for a systematic review and meta-analysis. BMJ Open. 2018; 8(5):e019719. https://doi.org/10.1136/bmjopen-2017-019719
Presta V, Figliuzzi I, Citoni B, Miceli F, Battistoni A, Musumeci MB, et al. Effects of different statin types and dosages on systolic/diastolic blood pressure: Retrospective analysis of 24‐hour ambulatory blood pressure database. J Clin Hypertens (Greenwich). 2018; 20(5):967–75. https://doi.org/10.1111/jch.13283
Schneider MP, Schmidt BM, John S, Schmieder RE. Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels. J Hypertens. 2011; 29(9):1757–64. https://doi.org/10.1097/hjh.0b013e32834a509a
Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006; 440:1217–21. https://doi.org/10.1038/nature04672
Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet. 2010; 375(9709):132–40. https://doi.org/10.1016/S0140-6736(09)61717-7
Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS, Stefanadis C. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol. 2009; 54(8):669–77. https://doi.org/10.1016/j.jacc.2009.03.076
Zheng D, Cai A, Xu R, Mai Z, Zhou Y, Zeng F, et al. Effects and potential mechanism of atorvastatin treatment on Lp-PLA2 in rats with dyslipidemia. Arch Med Sci. 2018; 14(3):629. https://dx.doi.org/10.5114%2Faoms.2017.69494
Murty MS, Sharma UK, Pandey VB, Kankare SB. Serum cystatin C as a marker of renal function in detection of early acute kidney injury. Indian J Nephrol. 2013; 23(3):180. https://doi.org/10.4103/0971-4065.111840
Manaktala R, Tafur-Soto JD, White CJ. Renal Artery Stenosis in the Patient with Hypertension: Prevalence, Impact and Management. Integr Blood Press Control. 2020; 13:71. https://dx.doi.org/10.2147%2FIBPC.S248579
Rodondi N, Marques-Vidal P, Butler J, Sutton-Tyrrell K, Cornuz J, Satterfield S, et al. Markers of atherosclerosis and inflammation for prediction of coronary heart disease in older adults.Am J Epidemiol. 2010; 171(5):540–9. https://dx.doi.org/10.1093%2Faje%2Fkwp428
Wang J, Tan GJ, Han LN, Bai YY, He M, Liu HB. Novel biomarkers for cardiovascular risk prediction. J Geriatr Cardiol. 2017; 14(2):135. https://doi.org/10.11909/j.issn.1671-5411.2017.02.008
Li H, Sun K, Zhao R, Hu J, Hao Z, Wang F, et al. Inflammatory biomarkers of coronary heart disease. Front Biosci (Schol Ed). 2018; 10(1):185–96. https://doi.org/10.2741/s508
Aziz RS, DizayeK. Diuretic effect of Adiantum capillus and its chemical constituents in hypertensive rats. International Journal of Pharmaceutical Research. 2019; 11(3).
Dizaye KF, Chalaby LA. Hypolipidemic efficacy of Trigonella Foenum seeds in comparison with Rosuvastatin and Fenofibrate in hyperlipidemic rats. World Family Medicine Journal: Incorporating the Middle East Journal of Family Medicine. 2015; 99(2431):1–9.
Dizaye KF, Hamad BA. Cardiovascular studies of white squill (Urginea maritima) extract. Zanco J Med Sci. 2010; 14(1 Special):20–7.
Griffiths PR, Lolait SJ, Pearce LE, McBryde FD, Paton JF, O’Carroll AM. Blockade of rostral ventrolateral medulla apelin receptors does not attenuate arterial pressure in SHR and L-NAME-induced hypertensive rats. Front Physiol. 2018; 9:1488. https://doi.org/10.3389/fphys.2018.01488
Dizaye KF, Ahmed SR. Combination of atorvastatin and fenofibrate altered androgenic activities of male rats. Zanco J Med Sci. 2019; 23(2):264–73. https://doi.org/10.15218/zjms.2019.034
Kopincová J, Púzserová A, Bernátová I. L-NAME in the cardiovascular system—nitric oxide synthase activator?.Pharmacol Rep. 2012; (3):511–20. https://doi.org/10.1016/s1734-1140(12)70846-0
Rees DD, Palmer RM, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 1990; 101(3):746–52. https://dx.doi.org/10.1111%2Fj.1476-5381.1990.tb14151.x
Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH. Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial. Arch Intern Med. 2008; 168(7):721–7. https://dx.doi.org/10.1001%2Farchinte.168.7.721
Alghamdi J, Alqadi A, Alharf A, Almuzzaini B, Mahmud A, Barhoumi T, et al. Blood pressure-lowering activity of statins: a systematic literature review and meta-analysis of placebo-randomized controlled trials. Eur J Clin Pharmacol. 2020; 76(12):1745–54. https://doi.org/10.1007/s00228-020-02965-2
Gorabi AM, Kiaie N, Hajighasemi S, Banach M, Penson PE, Jamialahmadi T, et al. Statin-induced nitric oxide signaling: Mechanisms and therapeutic implications. J Clin Med. 2019; 8(12):2051. https://doi.org/10.3390/jcm8122051
Banach M, Nikfar S, Rahimi R, Bielecka-Dabrowa A, Pencina MJ, Mikhailidis DP, et al. Lipid and Blood Pressure Meta-Analysis Collaboration Group. The effects of statins on blood pressure in normotensive or hypertensive subjects—a meta-analysis of randomized controlled trials. Int J Cardiol. 2013; 168(3):2816–24. https://doi.org/10.1016/j.ijcard.2013.03.068
Kanbay M, Yildirir A, Bozbas H, Ulus T, Bilgi M, Muderrisoglu H, et al. Statin therapy helps to control blood pressure levels in hypertensive dyslipidemic patients. Ren Fail. 2005; 27(3):297–303. https://doi.org/10.1081/JDI-56610
Koh KK, Quon MJ, Han SH, Ahn JY, Jin DK, Kim HS, et al. Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. x
Hypertension. 2005; 45(6):1088–93. https://doi.org/10.1161/01.HYP.0000166722.91714.ba
You T, Liu XG, Hou XD, Wang XK, Xie HH, Ding F, et al. Effect of statins on blood pressure: analysis on adverse events released by FDA. Clin Exp Hypertens. 2017; 39(4):325–9. https://doi.org/10.1080/10641963.2016.1254224
Feldstein CA. Statins in hypertension: are they a new class of antihypertensive agents? Am J Ther. 2010; 17(3):255–62. https://doi.org/10.1097/mjt.0b013e3181c0695e
Wierzbicki AS. Statins and hypertension. J Hum Hypertens. 2006; 20(8):554–6. https://doi.org/10.1038/sj.jhh.1002032
Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med. 2004; 351(25):2599–610. https://doi.org/10.1056/nejmoa040967
Chamarthi B, Williams GH, Ricchiuti V, Srikumar N, Hopkins PN, Luther JM, et al. Inflammation and hypertension: the interplay of interleukin-6, dietary sodium, and the renin-angiotensin system in humans. Am J Hypertens. 2011; 24(10):11438. https://dx.doi.org/10.1038%2Fajh.2011.113
Jayedi A, Rahimi K, Bautista LE, Nazarzadeh M, Zargar MS, Shab-Bidar S. Inflammation markers and risk of developing hypertension: a meta-analysis of cohort studies. Heart. 2019; 105(9):686–92. http://dx.doi.org/10.1136/heartjnl-2018-314216
Jalali MJ, Phadke MS. Assessment of endothelial dysfunction in health and disease; using various parameters.Indian J Clin Biochem 2011; 26(4):407–12. https://dx.doi.org/10.1007%2Fs12291-011-0140-4
Higashi Y, Kihara Y, Noma K. Endothelial dysfunction and hypertension in aging. Hypertens Res. 2012; 35(11):1039–47. https://doi.org/10.1038/hr.2012.138
S Antonopoulos A, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012; 18(11):1519–30. https://doi.org/10.2174/138161212799504803
Albert MA, Danielson E, Rifai N, Ridker PM, PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001; 286(1):64–70. https://doi.org/10.1001/jama.286.1.64
Sarlon-Bartoli G, Boudes A, Buffat C, Bartoli MA, Piercecchi-Marti MD, Sarlon E, et al. Circulating lipoprotein-associated phospholipase A2 in high-grade carotid stenosis: a new biomarker for predicting unstable plaque. Eur J Vasc Endovasc Surg. 2012; 43(2):154–9. https://doi.org/10.1016/j.ejvs.2011.10.009
Huang YQ, Jie LI, Chen JY, Tang ST, Huang C, Feng YQ. The relationship between soluble CD40 ligand level and atherosclerosis in white-coat hypertension. J Hum Hypertens. 2017; 32(1):40–5. https://www.nature.com/articles/s41371-017-0016-z
Sonmez A, Dogru T, Yilmaz MI, Ocal R, Ozgurtas T, Kilic S, Eyileten T, Tasci I, Erbil K, Kocar IH. Soluble CD40 ligand levels in patients with hypertension. Clin Exp Hypertens. 2005; 27(8):629–34. https://doi.org/10.1080/10641960500298673
Pamukcu B, Lip GY, Snezhitskiy V, Shantsila E. The CD40-CD40L system in cardiovascular disease. Ann Med. 2011; 43(5):331–40. https://doi.org/10.3109/07853890.2010.546362
Salminen M, Laine K, Korhonen P, Wasen E, Vahlberg T, Isoaho R, et al. Biomarkers of kidney function and prediction of death from cardiovascular and other causes in the elderly: a 9-year follow-up study. Eur J Intern Med. 2016; 33:98–101. https://doi.org/10.1016/j.ejim.2016.06.024
Willey JZ, Moon YP, Husain SA, Elkind MS, Sacco RL, Wolf M, et al. Creatinine versus cystatin C for renal function-based mortality prediction in an elderly cohort: The Northern Manhattan Study. PloS one. 2020; 15(1):e0226509. https://doi.org/10.1371/journal.pone.0226509
Shankar A, Teppala S. Relationship between serum cystatin C and hypertension among US adults without clinically recognized chronic kidney disease.J Am Soc Hypertens. 2011; 5(5):378–84. https://doi.org/10.1016/j.jash.2011.03.003
Zhao M, Che Q, Zhang Y, Qian X, Huang T. Expression and clinical significance of serum cystatin C in patients with hypertension and coronary heart disease. Medicine (Baltimore). 2020; 99(22):e20029. https://doi.org/10.1097/md.0000000000020029
Griffin KA. Hypertensive kidney injury and the progression of chronic kidney disease. Hypertension. 2017; 70(4):687–94. https://doi.org/10.1161/hypertensionaha.117.08314
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Kawa F. Dizaye, Begard O. Berzinji (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The copyright on any article published in Zanco J Med Sci is retained by the author(s) in agreement with the Creative Commons Attribution Non-Commercial ShareAlike License (CC BY-NC-SA 4.0).
