The Impact of Spironolactone on Markers of Myocardial Oxidative Status, Inflammation and Remodeling in Hyperthyroid Rats

Author(s): Fadia A Mayyas*, Ahmad I Aljohmani, Karem H Alzoubi

Journal Name: Current Molecular Pharmacology

Volume 13 , Issue 3 , 2020

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Abstract:

Background: Hyperthyroidism promotes the development and progression of cardiovascular diseases (CVD). Aldosterone, a key mediator of myocardial inflammation, oxidative stress and fibrosis, may be activated in hyperthyroidism.

Objective: To assess the impact of hyperthyroidism on aldosterone levels and myocardial oxidative status, inflammatory and fibrotic markers in hyperthyroid rats, and to test if the use of spironolactone (an aldosterone antagonist) attenuates these changes.

Methods: Adult Wistar rats were randomly distributed into 4 groups; controls, spironolactone treated rats (Spir, 50mg/kg/day), hyperthyroid rats (Hyper, daily intraperitoneal levothyroxine 0.3mg/kg/day), and spironolactone treated hyperthyroid rats (Hyper+Spir) for 4 weeks. Blood pressure (Bp), and levels of serum and myocardial aldosterone, oxidants/antioxidants, inflammatory and fibrotic markers were measured.

Results: Levothyroxine increased serum thyroid hormones and increased Bp, heart rate and heart to bodyweight ratio. Relative to control, serum aldosterone levels were increased in Hyper and Hyper+ Spir groups. In parallel, cardiac lipid peroxides and serum endothelin-1 were increased whereas cardiac superoxide dismutase, catalase, glutathione, and matrix metalloproteinase -2 were reduced in the Hyper group. Spironolactone decreased serum thyroid hormones and improved cardiac lipid peroxides and metalloproteinase -2 levels. The use of spironolactone decreased serum nitrite levels and increased cardiac SOD and glutathione. Cardiac levels of aldosterone, endothelin-1, transforming growth factor-beta and nitrite were similar among all groups.

Conclusion: Hyperthyroid status was associated with an increase in aldosterone and oxidant/ inflammatory biomarkers. The use of spironolactone enhanced antioxidant defenses. Aldosterone antagonists may serve as potential drugs to attenuate the development of cardiac disease in hyperthyroidism.

Keywords: Spironolactone, hyperthyroidism, aldosterone, cardiovascular disease, oxidative stress, fibrosis, inflammation.

[1]
Dimmeler, S. Cardiovascular disease review series. EMBO Mol. Med., 2011, 3(12), 697.
[http://dx.doi.org/10.1002/emmm.201100182] [PMID: 22113984]
[2]
Osuna, P.M.; Udovcic, M.; Sharma, M.D. Hyperthyroidism and the Heart. Methodist DeBakey Cardiovasc. J., 2017, 13(2), 60-63.
[http://dx.doi.org/10.14797/mdcj-13-2-60] [PMID: 28740583]
[3]
Cooper, D.S. Hyperthyroidism. Lancet, 2003, 362(9382), 459-468.
[http://dx.doi.org/10.1016/S0140-6736(03)14073-1] [PMID: 12927435]
[4]
Dörr, M.; Völzke, H. Cardiovascular morbidity and mortality in thyroid dysfunction. Minerva Endocrinol., 2005, 30(4), 199-216.
[PMID: 16319809]
[5]
Dillmann, W.H. Cellular action of thyroid hormone on the heart. Thyroid, 2002, 12(6), 447-452.
[http://dx.doi.org/10.1089/105072502760143809] [PMID: 12165105]
[6]
Sugamura, K.; Keaney, J.F., Jr Reactive oxygen species in cardiovascular disease. Free Radic. Biol. Med., 2011, 51(5), 978-992.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.05.004] [PMID: 21627987]
[7]
Vasan, R.S.; Sullivan, L.M.; Roubenoff, R.; Dinarello, C.A.; Harris, T.; Benjamin, E.J.; Sawyer, D.B.; Levy, D.; Wilson, P.W.; D’Agostino, R.B.; Framingham Heart, S. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation, 2003, 107(11), 1486-1491.
[http://dx.doi.org/10.1161/01.CIR.0000057810.48709.F6] [PMID: 12654604]
[8]
Parker, J.D.; Thiessen, J.J. Increased endothelin-1 production in patients with chronic heart failure. Am. J. Physiol. Heart Circ. Physiol., 2004, 286(3), H1141-H1145.
[http://dx.doi.org/10.1152/ajpheart.00239.2001] [PMID: 14766679]
[9]
Stewart, D.J.; Kubac, G.; Costello, K.B.; Cernacek, P. Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J. Am. Coll. Cardiol., 1991, 18(1), 38-43.
[http://dx.doi.org/10.1016/S0735-1097(10)80214-1] [PMID: 2050938]
[10]
Berk, B.C.; Fujiwara, K.; Lehoux, S. ECM remodeling in hypertensive heart disease. J. Clin. Invest., 2007, 117(3), 568-575.
[http://dx.doi.org/10.1172/JCI31044] [PMID: 17332884]
[11]
Iravanian, S.; Dudley, S.C., Jr The renin-angiotensin-aldosterone system (RAAS) and cardiac arrhythmias. Heart Rhythm, 2008, 5(6)(Suppl.), S12-S17.
[http://dx.doi.org/10.1016/j.hrthm.2008.02.025] [PMID: 18456194]
[12]
Mayyas, F.; Alzoubi, K.H.; Van Wagoner, D.R. Impact of aldosterone antagonists on the substrate for atrial fibrillation: aldosterone promotes oxidative stress and atrial structural/electrical remodeling. Int. J. Cardiol., 2013, 168(6), 5135-5142.
[http://dx.doi.org/10.1016/j.ijcard.2013.08.022] [PMID: 23993726]
[13]
Cachofeiro, V.; López-Andrés, N.; Miana, M.; Martín-Fernández, B.; de Las Heras, N.; Martínez, E.; Lahera, V.; Fortuño, M.A. Aldosterone and the cardiovascular system: a dangerous association. Horm. Mol. Biol. Clin. Investig., 2010, 4(2), 539-548.
[http://dx.doi.org/10.1515/HMBCI.2010.057] [PMID: 25961230]
[14]
Pu, Q.; Neves, M.F.; Virdis, A.; Touyz, R.M.; Schiffrin, E.L. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension, 2003, 42(1), 49-55.
[http://dx.doi.org/10.1161/01.HYP.0000078357.92682.EC] [PMID: 12782645]
[15]
Hirono, Y.; Yoshimoto, T.; Suzuki, N.; Sugiyama, T.; Sakurada, M.; Takai, S.; Kobayashi, N.; Shichiri, M.; Hirata, Y. Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: the possible role of local renin-angiotensin system. Endocrinology, 2007, 148(4), 1688-1696.
[http://dx.doi.org/10.1210/en.2006-1157] [PMID: 17218415]
[16]
Pitt, B.; Zannad, F.; Remme, W.J.; Cody, R.; Castaigne, A.; Perez, A.; Palensky, J.; Wittes, J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med., 1999, 341(10), 709-717.
[http://dx.doi.org/10.1056/NEJM199909023411001] [PMID: 10471456]
[17]
Burniston, J.G.; Saini, A.; Tan, L.B.; Goldspink, D.F. Aldosterone induces myocyte apoptosis in the heart and skeletal muscles of rats in vivo. J. Mol. Cell. Cardiol., 2005, 39(2), 395-399.
[http://dx.doi.org/10.1016/j.yjmcc.2005.04.001] [PMID: 15907929]
[18]
Mayyas, F.; Alzoubi, K.H.; Bonyan, R. The role of spironolactone on myocardial oxidative stress in rat model of streptozotocin-induced diabetes. Cardiovasc. Ther., 2017, 35(2)
[http://dx.doi.org/10.1111/1755-5922.12242] [PMID: 27992114]
[19]
Engels, K.; Rakov, H.; Zwanziger, D.; Hönes, G.S.; Rehders, M.; Brix, K.; Köhrle, J.; Möller, L.C.; Führer, D. Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice. Endocrine, 2016, 54(1), 47-54.
[http://dx.doi.org/10.1007/s12020-016-1020-8] [PMID: 27473100]
[20]
Mayyas, F.; Alzoubi, K.H.; Al-Taleb, Z. An evaluation of the effect of pentoxifylline on blood pressure and myocardial oxidative status following intake of western diet. Clin. Exp. Hypertens., 2015, 37(8), 666-673.
[http://dx.doi.org/10.3109/10641963.2015.1047944] [PMID: 26151826]
[21]
Bianco, A.C.; Anderson, G.; Forrest, D.; Galton, V.A.; Gereben, B.; Kim, B.W.; Kopp, P.A.; Liao, X.H.; Obregon, M.J.; Peeters, R.P.; Refetoff, S.; Sharlin, D.S.; Simonides, W.S.; Weiss, R.E.; Williams, G.R. American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid, 2014, 24(1), 88-168.
[http://dx.doi.org/10.1089/thy.2013.0109] [PMID: 24001133]
[22]
Semler, D.E.; Chengelis, C.P.; Radzialowski, F.M. The effects of chronic ingestion of spironolactone on serum thyrotropin and thyroid hormones in the male rat. Toxicol. Appl. Pharmacol., 1989, 98(2), 263-268.
[http://dx.doi.org/10.1016/0041-008X(89)90231-7] [PMID: 2496489]
[23]
De Leo, S.; Lee, S.Y.; Braverman, L.E. Hyperthyroidism. Lancet, 2016, 388(10047), 906-918.
[http://dx.doi.org/10.1016/S0140-6736(16)00278-6] [PMID: 27038492]
[24]
Kumar, A.; Sinha, R.A.; Tiwari, M.; Singh, R.; Koji, T.; Manhas, N.; Rastogi, L.; Pal, L.; Shrivastava, A.; Sahu, R.P.; Godbole, M.M. Hyperthyroidism induces apoptosis in rat liver through activation of death receptor-mediated pathways. J. Hepatol., 2007, 46(5), 888-898.
[http://dx.doi.org/10.1016/j.jhep.2006.12.015] [PMID: 17321637]
[25]
Zhang, Y.; Dedkov, E.I.; Teplitsky, D.; Weltman, N.Y.; Pol, C.J.; Rajagopalan, V.; Lee, B.; Gerdes, A.M. Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats. Circ Arrhythm Electrophysiol, 2013, 6(5), 952-959.
[http://dx.doi.org/10.1161/CIRCEP.113.000502] [PMID: 24036190]
[26]
Weltman, N.Y.; Wang, D.; Redetzke, R.A.; Gerdes, A.M. Longstanding hyperthyroidism is associated with normal or enhanced intrinsic cardiomyocyte function despite decline in global cardiac function. PLoS One, 2012, 7(10), e46655
[http://dx.doi.org/10.1371/journal.pone.0046655] [PMID: 23056390]
[27]
Boldt, A.; Wetzel, U.; Weigl, J.; Garbade, J.; Lauschke, J.; Hindricks, G.; Kottkamp, H.; Gummert, J.F.; Dhein, S. Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease. J. Am. Coll. Cardiol., 2003, 42(10), 1785-1792.
[http://dx.doi.org/10.1016/j.jacc.2003.07.014] [PMID: 14642689]
[28]
Sun, Y.; Zhang, J.; Lu, L.; Chen, S.S.; Quinn, M.T.; Weber, K.T. Aldosterone-induced inflammation in the rat heart : role of oxidative stress. Am. J. Pathol., 2002, 161(5), 1773-1781.
[http://dx.doi.org/10.1016/S0002-9440(10)64454-9] [PMID: 12414524]
[29]
Marchant, C.; Brown, L.; Sernia, C. Renin-angiotensin system in thyroid dysfunction in rats. J. Cardiovasc. Pharmacol., 1993, 22(3), 449-455.
[http://dx.doi.org/10.1097/00005344-199309000-00016] [PMID: 7504137]
[30]
Kim, B.; Carvalho-Bianco, S.D.; Larsen, P.R. Thyroid hormone and adrenergic signaling in the heart. Arq. Bras. Endocrinol. Metabol, 2004, 48(1), 171-175.
[http://dx.doi.org/10.1590/S0004-27302004000100019] [PMID: 15611830]
[31]
Williams, T.L.; Elliott, J.; Syme, H.M. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J. Vet. Intern. Med., 2013, 27(3), 522-529.
[http://dx.doi.org/10.1111/jvim.12062] [PMID: 23517505]
[32]
Asayama, K.; Dobashi, K.; Hayashibe, H.; Kato, K. Effects of beta-adrenergic blockers with different ancillary properties on lipid peroxidation in hyperthyroid rat cardiac muscle. Endocrinol. Jpn., 1989, 36(5), 687-694.
[http://dx.doi.org/10.1507/endocrj1954.36.687] [PMID: 2575990]
[33]
Venditti, P.; Di Meo, S. Thyroid hormone-induced oxidative stress. Cell. Mol. Life Sci., 2006, 63(4), 414-434.
[http://dx.doi.org/10.1007/s00018-005-5457-9] [PMID: 16389448]
[34]
Huffman, L.J.; Judy, D.J.; Rao, K.M.; Frazer, D.G.; Goldsmith, W.T. Lung responses to hypothyroidism, hyperthyroidism, and lipopolysaccharide challenge in rats. J. Toxicol. Environ. Health A, 2000, 61(7), 623-639.
[http://dx.doi.org/10.1080/00984100050194135] [PMID: 11127416]
[35]
Shinohara, R.; Mano, T.; Nagasaka, A.; Hayashi, R.; Uchimura, K.; Nakano, I.; Watanabe, F.; Tsugawa, T.; Makino, M.; Kakizawa, H.; Nagata, M.; Iwase, K.; Ishizuki, Y.; Itoh, M. Lipid peroxidation levels in rat cardiac muscle are affected by age and thyroid status. J. Endocrinol., 2000, 164(1), 97-102.
[http://dx.doi.org/10.1677/joe.0.1640097] [PMID: 10607942]
[36]
Battistini, B.; D’Orléans-Juste, P.; Sirois, P. Endothelins: circulating plasma levels and presence in other biologic fluids. Lab. Invest., 1993, 68(6), 600-628.
[PMID: 8515652]
[37]
Mayyas, F.; Niebauer, M.; Zurick, A.; Barnard, J.; Gillinov, A.M.; Chung, M.K.; Van Wagoner, D.R. Association of left atrial endothelin-1 with atrial rhythm, size, and fibrosis in patients with structural heart disease. Circ Arrhythm Electrophysiol, 2010, 3(4), 369-379.
[http://dx.doi.org/10.1161/CIRCEP.109.924985] [PMID: 20495015]
[38]
Mayyas, F.; Saadeh, N.; Al-Muqbel, K.; Van Wagoner, D.R. Plasma endothelin-1 levels are increased in atrial fibrillation patients with hyperthyroidism. PLoS One, 2018, 13(12)e0208206
[http://dx.doi.org/10.1371/journal.pone.0208206] [PMID: 30513109]
[39]
Chu, C.H.; Lee, J.K.; Keng, H.M.; Chuang, M.J.; Lu, C.C.; Wang, M.C.; Sun, C.C.; Wei, M.C.; Lam, H.C. Hyperthyroidism is associated with higher plasma endothelin-1 concentrations. Exp. Biol. Med. (Maywood), 2006, 231(6), 1040-1043.
[PMID: 16741045]
[40]
Wong, S.; Brennan, F.E.; Young, M.J.; Fuller, P.J.; Cole, T.J. A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology, 2007, 148(4), 1511-1517.
[http://dx.doi.org/10.1210/en.2006-0965] [PMID: 17218419]
[41]
Williams, J.S. Evolving research in nongenomic actions of aldosterone. Curr. Opin. Endocrinol. Diabetes Obes., 2013, 20(3), 198-203.
[http://dx.doi.org/10.1097/MED.0b013e328360c200] [PMID: 23519092]
[42]
Grossmann, C.; Benesic, A.; Krug, A.W.; Freudinger, R.; Mildenberger, S.; Gassner, B.; Gekle, M. Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol. Endocrinol., 2005, 19(7), 1697-1710.
[http://dx.doi.org/10.1210/me.2004-0469] [PMID: 15761031]
[43]
Kritis, A.A.; Gouta, C.P.; Liaretidou, E.I.; Kallaras, K.I. Latest aspects of aldosterone actions on the heart muscle. J. Physiol. Pharmacol., 2016, 67(1), 21-30.
[PMID: 27010892]
[44]
van der Veen, B.S.; de Winther, M.P.; Heeringa, P. Myeloperoxidase: molecular mechanisms of action and their relevance to human health and disease. Antioxid. Redox Signal., 2009, 11(11), 2899-2937.
[http://dx.doi.org/10.1089/ars.2009.2538] [PMID: 19622015]
[45]
Barut, F.; Ozacmak, V.H.; Turan, I.; Sayan-Ozacmak, H.; Aktunc, E. Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats. Clin. Invest. Med., 2016, 39(1), E15-E24.
[http://dx.doi.org/10.25011/cim.v39i1.26326] [PMID: 26833169]
[46]
Doetschman, T.; Barnett, J.V.; Runyan, R.B.; Camenisch, T.D.; Heimark, R.L.; Granzier, H.L.; Conway, S.J.; Azhar, M. Transforming growth factor beta signaling in adult cardiovascular diseases and repair. Cell Tissue Res., 2012, 347(1), 203-223.
[http://dx.doi.org/10.1007/s00441-011-1241-3] [PMID: 21953136]
[47]
Seeland, U.; Haeuseler, C.; Hinrichs, R.; Rosenkranz, S.; Pfitzner, T.; Scharffetter-Kochanek, K.; Böhm, M. Myocardial fibrosis in transforming growth factor-beta(1) (TGF-beta(1)) transgenic mice is associated with inhibition of interstitial collagenase. Eur. J. Clin. Invest., 2002, 32(5), 295-303.
[http://dx.doi.org/10.1046/j.1365-2362.2002.00985.x] [PMID: 12027867]
[48]
Wang, M.; Kim, S.H.; Monticone, R.E.; Lakatta, E.G. Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension, 2015, 65(4), 698-703.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.03618] [PMID: 25667214]
[49]
Zervoudaki, A.; Economou, E.; Stefanadis, C.; Pitsavos, C.; Tsioufis, K.; Aggeli, C.; Vasiliadou, K.; Toutouza, M.; Toutouzas, P. Plasma levels of active extracellular matrix metalloproteinases 2 and 9 in patients with essential hypertension before and after antihypertensive treatment. J. Hum. Hypertens., 2003, 17(2), 119-124.
[http://dx.doi.org/10.1038/sj.jhh.1001518] [PMID: 12574790]
[50]
Hori, Y.; Yoshioka, K.; Kanai, K.; Hoshi, F.; Itoh, N.; Higuchi, S-I. Spironolactone Decreases Isoproterenol-Induced Ventricular Fibrosis and Matrix Metalloproteinase-2 in Rats, 2011, Vol. 34, 61-65.
[51]
Ferreira, J.P.; Santos, M.; Oliveira, J.C.; Marques, I.; Bettencourt, P.; Carvalho, H. Influence of spironolactone on matrix metalloproteinase-2 in acute decompensated heart failure. Arq. Bras. Cardiol., 2015, 104(4), 308-314.
[PMID: 25993594]
[52]
Rude, M.K.; Duhaney, T.A.; Kuster, G.M.; Judge, S.; Heo, J.; Colucci, W.S.; Siwik, D.A.; Sam, F. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension, 2005, 46(3), 555-561.
[http://dx.doi.org/10.1161/01.HYP.0000176236.55322.18] [PMID: 16043662]


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VOLUME: 13
ISSUE: 3
Year: 2020
Page: [206 - 215]
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DOI: 10.2174/1874467212666191113150553
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