Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats
- 115 Downloads
Compound 21 (C21), selective AT2 receptor agonist, has cardioprotective effects in experimental models of hypertension and myocardial infarction. The aims of the study was to evaluate the effect of C21, losartan, or both in Zucker diabetic fatty (ZDF) rats (type 2 diabetes) on (1) the prevention of myocardial hypertrophy; (2) myocardial expression of phosphatase and tensin homolog (PTEN), a target gene of miR-30a-3p, involved in myocardial remodelling.
Experiments were performed in ZDF (n = 33) and in control Lean (8) rats. From the 6th to the 20th week of age, we administered C21 (0.3 mg/kg/day) to 8 ZDF rats. 8 ZDF rats were treated with losartan (10 mg/kg/day), 8 rats underwent combination treatment, C21+ losartan, and 9 ZDF rats were left untreated. Blood glucose and blood pressure were measured every 4 weeks. At the end of the study the hearts were removed, the apex was cut for the quantification of PTEN mRNA and miR-30a-3p expression (realtime-PCR). Myocardial hypertrophy was evaluated by histomorphometric analysis, and nitrotyrosine expression (as marker of oxidative stress) by immunohistochemistry.
ZDF rats had higher blood glucose (p < 0.0001) with respect to control Lean rats, while blood pressure did not change. Both parameters were not modified by C21 treatment, while losartan and losartan + C21 reduced blood pressure in ZDF rats (p < 0.05). miR-30a-3p expression was increased in ZDF rats (p < 0.01) and PTEN mRNA expression was decreased (p < 0.05). ZDF rats developed myocardial hypertrophy (p < 0.01) and increased oxidative stress (p < 0.01), both were prevented by C21 or losartan, or combination treatment. C21 or losartan normalized the expression of miR-30a-3p and PTEN.
Activation of AT2 receptors or AT1 receptor blockade prevents the development of myocardial hypertrophy in ZDF rats. This occurs through the modulation of the miR-30a-3p/PTEN interaction.
KeywordsDiabetes Myocardial hypertrophy Angiotensin type 1 receptors Angiotensin type 2 receptors MicroRNA Zucker diabetic fatty rats Compound 21
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Animal studies were in conformity with the Institutional Guidelines in compliance with National laws and policies (D.L.n. 116, Gazzetta Ufficiale della Repubblica Italiana, suppl.40, Feb.18, 1992) and experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
For this type of study (experimental study on animal model) it is not required.
- 7.Mancia G, Fagard R, Narkiewicz K et al (2013) 2013 ESH/ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 31:1281–1357. https://doi.org/10.1097/01.hjh.0000431740.32696.cc CrossRefGoogle Scholar
- 8.Borghi C, SIIA Task Force, Rossi F, SIF Task Force (2015) Role of the renin-angiotensin-aldosterone system and its pharmacological inhibitors in cardiovascular diseases: complex and critical issues. High Blood Press Cardiovasc Prev 22:429–444. https://doi.org/10.1007/s40292-015-0120-5 CrossRefGoogle Scholar
- 11.Rompe F, Artuc M, Hallberg A et al (2010) Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB. Hypertension 55:924–931. https://doi.org/10.1161/HYPERTENSIONAHA.109.147843 CrossRefGoogle Scholar
- 13.Lauer D, Slavic S, Sommerfeld M et al (2014) Angiotensin type 2 receptor stimulation ameliorates left ventricular fibrosis and dysfunction via regulation of tissue inhibitor of matrix metalloproteinase 1/matrix metalloproteinase 9 axis and transforming growth factor β1 in the rat heart. Hypertension 63:e60–e67. https://doi.org/10.1161/HYPERTENSIONAHA.113.02522 CrossRefGoogle Scholar
- 17.Paulis L, Becker ST, Lucht K et al (2012) Direct angiotensin II type 2 receptor stimulation in Nω-nitro-L-arginine-methyl ester-induced hypertension. The effect on pulse wave velocity and aortic remodeling. Hypertension 59:485–492. https://doi.org/10.1161/HYPERTENSIONAHA.111.185496 CrossRefGoogle Scholar
- 18.Rehman A, Leibowitz A, Yamamoto N, Rautureau Y, Paradis P, Schiffrin EL (2012) Angiotensin type 2 receptor agonist compound 21 reduces vascular injury and myocardial fibrosis in stroke-prone spontaneously hypertensive rats. Hypertension 59:291–299. https://doi.org/10.1161/HYPERTENSIONAHA.111.180158 CrossRefGoogle Scholar
- 32.Castoldi G, di Gioia CR, Giollo F et al (2016) Different regulation of miR-29a-3p in glomeruli and tubules in an experimental model of angiotensin II-dependent hypertension: potential role in renal fibrosis. Clin Exp Pharmacol Physiol 43:335–342. https://doi.org/10.1111/1440-1681.12532 CrossRefGoogle Scholar
- 36.Shum M, Pinard S, Guimond MO et al (2013) Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats. Am J Physiol Endocrinol Metab 304(2):E197–E210. https://doi.org/10.1152/ajpendo.00149.2012 CrossRefGoogle Scholar
- 45.Savoia C, Ebrahimian T, He Y, Gratton JP, Schiffrin EL, Touyz RM (2006) Angiotensin II/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase. J Hypertens 24(12):2417–2422. https://doi.org/10.1097/01.hjh.0000251902.85675.7e CrossRefGoogle Scholar