Amlexanox Exhibits Cardioprotective Effects in 5/6 Nephrectomized Rats
DOI:
https://doi.org/10.1590/s2175-97902022e20978Palavras-chave:
Amlexanox, Cardiorenal syndrome, β-Arrestin-2Resumo
Cardiorenal syndrome is a life-threatening condition. The aim of the current study was to determine the cardioprotective effects of amlexanox in 5/6 nephrectomized rats. Rats were randomly assigned to three groups: sham, 5/6 nephrectomized rats, and amlexanox-treated 5/6 nephrectomized group. Amlexanox (25 mg/kg/day, i.p.) administration was started just after surgery and continued for 10 weeks. After treatment, kidney function (serum creatinine and urea) and blood pressure (systolic and diastolic) were measured. Heart weight (normalized to tibial length) and fibrosis area percentage were measured. Serum brain natriuretic peptide (BNP, heart failure marker) and cardiac levels of β1-adrenergic receptor (β1AR), β-arrestin-2, phosphatidylinositol-4,5-bisphosphate (PIP2), diacylglycerol (DAG), pS473 Akt (a survival marker), and caspase-3 activity (an apoptosis marker) were also measured. The 5/6 nephrectomy caused renal impairment, cardiac fibrosis, apoptosis, and heart failure indicated by down- regulation of cardiac β1AR down-stream signals compared with those in the sham group. Interestingly, amlexanox significantly reduced all cardiopathological changes induced after 10 weeks of 5/6 nephrectomy. Amlexanox showed potent cardiac antifibrotic and antiapoptotic effects in 5/6 nephrectomized rats, which were associated with reduced heart failure. To our knowledge, this is the first study that addresses the potent in vivo cardioprotective effects of amlexanox.
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Bathgate-Siryk A, Dabul S, Pandya K, Walklett K, Rengo G, Cannavo A, et al. Negative impact of β-arrestin-1 on post- myocardial infarction heart failure via cardiac and adrenal- dependent neurohormonal mechanisms. Hypertension. 2014;63(2):404-412.
Bell J. Amlexanox for the treatment of recurrent aphthous ulcers. Clin Drug Investig. 2005;25(9):555-566.
Boccella N, Paolillo R, Perrino C. Epac1 inhibition as a novel cardioprotective strategy: lights and shadows on GRK5 canonical and non-canonical functions. Cardiovasc Res. 2019;115(12):1684-1686.
Carlstrom M, Montenegro M. Therapeutic value of stimulating the nitrate-nitrite-nitric oxide pathway to attenuate oxidative stress and restore nitric oxide bioavailability in cardiorenal disease. J Intern Med. 2019;285(1):2-18.
Chen EP, Bittner HB, Akhter SA, Koch WJ, Davis RD. Myocardial function in hearts with transgenic overexpression of the g protein-coupled receptor kinase 5. Ann Thorac Surg. 2001;71(4):1320-1324.
Hattori Y, Michel MC. G protein-coupled receptor kinases (GRKS) and β-arrestins: New insights into disease regulators. Front Pharmacol. 2019;10:1654.
Homan KT, Wu E, Cannavo A, Koch WJ, Tesmer JJ. Identification and characterization of amlexanox as a g protein-coupled receptor kinase 5 inhibitor. Molecules. 2014;19(10):16937-16949.
Hsu HT, Tseng YT, Wong WJ, Liu CM, Lo YC. Resveratrol prevents nanoparticles-induced inflammation and oxidative stress via downregulation of PKC-α and NADPH oxidase in lung epithelial a549 cells. BMC Complement Altern Med. 2018;18(1):1-13.
Ibrahim WS, Ibrahim IA-H, Mahmoud MF, Mahmoud AA. Carvedilol diminishes cardiac remodeling induced by high-fructose/high-fat diet in mice via enhancing cardiac β-arrestin2 signaling. J Cardiovasc Pharmacol Ther. 2020; 25(4):354-363.
Khoury S, Steinvil A, Gal-Oz A, Margolis G, Hochstatd A, Topilsky Y, et al. Association between central venous pressure as assessed by echocardiography, left ventricular function and acute cardio-renal syndrome in patients with st segment elevation myocardial infarction. Clin Res Cardiol. 2018;107(10):937-944.
Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, et al. A grk5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure. Nat Med. 2008;14(5):510-517.
Linssen G, Jaarsma T, Hillege H, Voors A,van Veldhuisen D. A comparison of the prognostic value of bnp versus nt- probnp after hospitalisation for heart failure. Neth Heart J. 2018;26(10):486-492.
Lučić I, Truebestein L, Leonard TA. Novel features of DAG- activated PKC isozymes reveal a conserved 3-d architecture. J Mol Biol. 2016;428(1):121-141.
McCrink KA, Maning J, Vu A, Jafferjee M, Marrero C, Brill A, et al. Β-arrestin2 improves post-myocardial infarction heart failure via sarco (endo) plasmic reticulum Ca2+- ATPase-dependent positive inotropy in cardiomyocytes. Hypertension . 2017;70(5):972-981.
Mohamed RM, Morimoto S, Ibrahim IAH, Zhan DY, Du CK, Arioka M, et al. Gsk-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2016;310(11):H1808-H1815.
Mohammed SG, Ibrahim IAH, Mahmoud MF, Mahmoud AA. Carvedilol protects against hepatic ischemia/ reperfusion injury in high-fructose/high-fat diet-fed mice: Role of g protein-coupled receptor kinase 2 and 5. Toxicol Appl Pharmacol. 2019;382:114750.
Mucke HA. Drug repurposing patent applications April- June 2018. Assay Drug Dev Technol. 2018;16(7):420-6.
Nelson CD, Kovacs JJ, Nobles KN, Whalen EJ, Lefkowitz RJ. Β-arrestin scaffolding of phosphatidylinositol 4-phosphate 5-kinase iα promotes agonist-stimulated sequestration of the β2-adrenergic receptor. J Biol Chem. 2008;283(30):21093- 21101.
Pallangyo P, Fredrick F, Bhalia S, Nicholaus P, Kisenge P, Mtinangi B, et al. Cardiorenal anemia syndrome and survival among heart failure patients in Tanzania: A prospective cohort study. BMC Cardiovasc Disord. 2017;17(1):59.
Patial S, Shahi S, Saini Y, Lee T, Packiriswamy N, Appledorn DM, et al. G-protein coupled receptor kinase 5 mediates lipopolysaccharide-induced nfκb activation in primary macrophages and modulates inflammation in vivo in mice. J Cell Physiol. 2011;226(5):1323-1333.
Rababa’h AM, Guillory AN, Mustafa R, Hijjawi T. Oxidative stress and cardiac remodeling: An updated edge. Curr Cardiol Rev. 2018;14 (1):53-59.
Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nat Med. 2013;19(3):313-321.
Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52(19):1527-1539.
Santulli G, Iaccarino G. Adrenergic signaling in heart failure and cardiovascular aging. Maturitas. 2016;93:65-72.
Suresh H, Arun B, Moger V, Swamy M. Cardiorenal syndrome type 4: A study of cardiovascular diseases in chronic kidney disease. Indian Heart J. 2017;69(1):11-16.
Švíglerová J, Kuncova J, Nalos L, Tonar Z, Rajdl D, Štengl M. Cardiovascular parameters in rat model of chronic renal failure induced by subtotal nephrectomy. Physiological research. 2010;59( Suppl 1):S81-S88.
Ungerer M, Parruti G, Böhm M, Puzicha M, DeBlasi A, Erdmann E, et al. Expression of beta-arrestins and beta- adrenergic receptor kinases in the failing human heart. Circ Res. 1994;74(2):206-213.
Velmurugan BK, Baskaran R,Huang C-Y. Detailed insight on β-adrenoceptors as therapeutic targets. Biomed Pharmacother. 2019;117:109039.
Vinod P, Krishnappa V, Chauvin AM, Khare A, Raina R. Cardiorenal syndrome: Role of arginine vasopressin and vaptans in heart failure. Cardiol Res. 2017;8(3):87-95.
Yang HQ, Zhou P, Wang LP, Zhao YT, Ren YJ, Guo YB, et al. Compartmentalized β1-adrenergic signalling synchronizes excitation-contraction coupling without modulating individual ca2+ sparks in healthy and hypertrophied cardiomyocytes. Cardiovasc Res. 2020;116(13):2069-2080.
Yu L, Huang B, Wang Z, Wang S, Wang M, Li X, et al. Impacts of renal sympathetic activation on atrial fibrillation: The potential role of the autonomic cross talk between kidney and heart. J Am Heart Assoc. 2017;6(3):e004716.
Zipursky RT, Press MC, Srikanthan P, Gornbein J, McClelland R, Watson K, et al. Relation of stress hormones (urinary catecholamines/cortisol) to coronary artery calcium in men versus women (from the multi-ethnic study of atherosclerosis [mesa]). Am J Cardiol. 2017;119(12):1963- 1971.
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