Abstract
Triiodothyronine (T3) and renin–angiotensin system (RAS) are functionally related in cardiovascular system. Recently, in an in vivo myocardial ischemia/reperfusion (I/R) model in rats, we showed that T3 treatment improved the post-ischemic recovery of cardiac function. In the present study, we used the same experimental model of regional I/R, obtained by 30 min occlusion of the left descending coronary artery, followed by 3-days of reperfusion, to investigate the effect of 48-h treatment (started 1 day after ischemia) with 6 µg/kg/day T3 or vehicle. T3 was delivered by constant subcutaneous infusion via miniosmotic pump. In particular, aim of this work is to evaluate the effects of T3 on the gene expression of the main receptors and enzymes involved in the two cardiac arms of RAS in an in vivo rat model of I/R: AT1R-ACE (detrimental arm) and AT2R/MAS1-ACE2 (protective arm). Gene expression was evaluated by Real-Time PCR in infarct zone (Area-At-Risk: AAR) and in tissues distant from ischemic wound (Remote Zone: RZ). Three different rat groups were used: sham-operated; I/R and I/R + T3. Main result of the study is the opposite response of AT1R and AT2R/MAS1 expression to I/R procedure and to T3 administration after I/R in both AAR and RZ. Moreover, T3 significantly increased ACE and ACE2 enzyme expression in AAR and RZ. This study reveals that T3 stimulates the expression of protective genes related to RAS such as AT2R/MAS1-ACE2 mainly in BZ, suggesting that, at least in part, T3 could be involved in the local cardiac ameliorative response to I/R procedure.
Similar content being viewed by others
References
Lang CC, Struthers AD (2013) Targeting the renin-angiotensin-aldosterone system in heart failure. Nat Rev Cardiol 10:125–134. https://doi.org/10.1038/nrcardio.2012.196
Barreto-Chaves ML, Carrillo-Sepulveda MA Gomes MS, Diniz DA (2010) Carneiro-Ramos. GP. The crosstalk between thyroid hormone and the renin-angiotensin system. Vasc Pharmacol 52:166–170. https://doi.org/10.1016/j.vph.2009.10.009
Tavares FM, da Silva IB, Gomes DA, Barreto-Chaves MLM (2013) Angiotensin II type 2 receptor (AT2R) is associated with increased tolerance of the hyperthyroid heart to ischemia-reperfusion. Cardiovasc Drugs Ther 27:393–402. https://doi.org/10.1007/s10557-013-6473-x
De Mello WC, Re RN (2009) Systemic versus local renin angiotensin systems. An overview. In: De Mello WC, Frohlich ED (eds) Renin angiotensin system and cardiovascular disease. Humana Press, New York, pp 1–5
Pearch MJ (1997) Renin-angiotensin system: biochemistry and mechanism of action. Physiol Rev 52:166–170
Steckelings UM, Kaschina E, Unger T (2005) The AT2R receptor-A matter of love and hate. Peptides 26:1401–1409. https://doi.org/10.1016/j.peptides.2005.03.010
Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE (2008) AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Therapeut 120:292–316. https://doi.org/10.1016/j.pharmthera.2008.08.009
Bader M (2013) ACE2, angiotensin-(1–7), and Mas: the other side of the coin. Pflugers Arch 465:79–85. https://doi.org/10.1007/s00424-012-1120-0
Steckelings UM, Unger T (2012) Angiotensin II type 2 receptor agonists where should they be applied? Expert Opin Investig Drugs 21:763–766. https://doi.org/10.1517/13543784.2012.664131
Pernomian L, Pernomian L, Baraldi C, Restini A (2014) Counter-regulatory effects played by the ACE-Ang II-AT1 and ACE2-Ang-(1–7)-Mas axes on the reactive oxygen species-mediated control of vascular function: perspectives to pharmacological approaches in controlling vascular complications. Vasa 43:404–414. https://doi.org/10.1024/0301-1526/a000387
Swynghedauw B (1999) Molecular mechanisms of myocardial remodeling. Physiol Rev 79:215–262
Pantos C, Mourouzis IS, Tzeis SM, Malliopoulou V, Cokkinos DD, Asimacopoulos P, Carageorgiou HC, Varonos DD, Cokkinos DV (2000) Propranolol diminishes cardiac hypertrophy but does not abolish acceleration of the ischemic contracture in hyperthyroid hearts. J Cardiovasc Pharmacol 36:384–389
Mann DL (2005) Left ventricular size and shape: determinants of mechanical signal transduction pathways. Heart Fail Rev 10:95–100. https://doi.org/10.1007/s10741-005-4636-y
Sehgal S, Drazner MH (2007) Left ventricular geometry: does shape matter? Am Heart J 153:153–155. https://doi.org/10.1016/j.ahj.2006.10.026
Yoshiyama M, Kim S, Yamagishi H, Omura T, Tani T, Yanagi S, Toda I, Teragaki M, Akioka K, Takeuchi K (1994) Cardioprotective effect of the angiotensin II type I receptor antagonist TCV-116 on ischemia-reperfusion injury. Am Heart J 128:1–6
Xu Y, Kumar D, Dyck JR, Ford WR, Clanachan AS, Lopaschuk GD, Jugdutt BI (2002) AT(1) and AT(2) receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts. Am J Physiol Heart Circ Physiol 282:H1206-H1215. https://doi.org/10.1152/ajpheart.00839.2000
Sabatino L, Kusmic C, Nicolini G, Amato R, Casini G, Iervasi G, Balzan S (2016) T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle. J Mol Endocrinol 57:139–149. https://doi.org/10.1530/JME-16-0118
Saba A, Donzelli R, Colligiani D, Raffaelli A, Nannipieri M, Kusmic C, Dos Remedios CG, Simonides WS, Iervasi G, Zucchi R (2014) Quantification of thyroxine and 3,5,3′-triiodo-thyronine in human and animal hearts by a novel liquid chromatography-tandem mass spectrometry method. Horm Metab Res 46:628–634. https://doi.org/10.1055/s-0034-1368717
Rajagopalan V, Zhang Y, Ojamaa K, Chen YF, Pingitore A, Pol CJ, Saunders D, Balasubramanian K, Towner RA, AM Gerdes (2016) Safe oral triiodo-L-thyronine therapy protects from post-infarct cardiac dysfunction and arrhythmias without cardiovascular adverse effects. PLoS ONE 11:e0151413
Pantos C, Paizis I, Mourouzis I, Moraitis P, Tzeis S, Karamanoli E, Mourouzis C, Karageorgiou H, Cokkinos DV (2005) Blockade of angiotensin II type 1 receptor diminishes cardiac hypertrophy, but does not abolish thyroxin-induced preconditioning. Horm Metab Res 37:500–504. https://doi.org/10.1055/s-0034-1368717
Tavares FM, da Silva IB, Gomes DA, Barreto-Chaves ML (2013) Angiotensin II type 2 receptor (AT2R) is associated with increased tolerance of the hyperthyroid heart to ischemia-reperfusion. Cardiovasc Drugs Ther 27:393–402. https://doi.org/10.1007/s10557-013-6473-x
Grady EF, Sechi LA, Griffin CA, Schambelan M, Kalinyak JE (1991) Expression of AT2 receptors in the developing rat fetus. J Clin Invest 88:921–933. https://doi.org/10.1172/JCI115395
Ohshima K, Mogi M, Nakaoka H, Iwanami J, Min L-J, Kanno H, Tsukuda K, Chisaka T, Bai H-Y, Wang X-L, Ogimoto A, Higaki J, Horiuchi M (2014) Possible role of Angiotensin-Converting-Enzyme 2 and activation of angiotensin II type 2 receptor by angiotensin-(1–7) in improvement of vascular remodeling by angiotensin II type 1 receptor blockade. Hypertension 63:e53–e59. https://doi.org/10.1161/hypertensionaha.113.02426
Yang B, Li D, Phillips MI, Mehta P, Mehta JL (1998) Myocardial angiotensin II receptor expression and ischemia-infusion injury. Vasc Med 3:121–130
Lax CJ, Domenighetti AA, Pavia JM, Di Nicolantonio R, Curl CL, Morris MJ, Delbridge LMD (2004) Transitory reduction in angiotensin AT2 receptor expression levels in postinfarct remodelling in rat myocardium. Clin Exp Pharmacol Physiol 31:512–517. https://doi.org/10.1111/j.1440-1681.2004.04034.x
Mendoza-Torres E, Oyarzùn A, Mondaca-Ruff D, Azocar A, Castro PF, Jalil JE, Chiong M, Lavandero S, Ocaranza MP (2015) ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension. Ther Adv Cardiovasc Dis 9:217–237. https://doi.org/10.1177/1753944715597623
Hu LW, Benvenuti LA, Liberti EA, Carneiro-Ramos MS, Barreto-Chaves ML (2003) Thyroxine-induced cardiac hypertrophy: influence of adrenergic nervous system versus renin-angiotensin system on myocyte remodeling. Am J Physiol Regul Integr Comp Physiol 285:R1473-R1480. https://doi.org/10.1152/ajpregu.00269.2003
Carneiro-Ramos MS, Diniz GP, Almeida J, Vieira RIP, Pinheiro SVB, Santos RA, Barreto-Chaves MLM (2007) Cardiac angiotensin II type I and type II receptors are increased in rats submitted to experimental hypothyroidism. J Physiol 583:213–223. https://doi.org/10.1113/jphysiol.2007.134080
Acknowledgements
This work was supported by Tuscany Region Research Grant (DGR 1157/2011) “Study of the molecular, biochemical and metabolic mechanisms involved in the cardioprotective effect of T3”.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflicts of interest to declare.
Rights and permissions
About this article
Cite this article
Sabatino, L., Balzan, S., Kusmic, C. et al. Modification of gene expression profiling related to renin–angiotensin system in an ischemia/reperfusion rat model after T3 infusion. Mol Cell Biochem 449, 277–283 (2018). https://doi.org/10.1007/s11010-018-3364-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-018-3364-2