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Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats

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Abstract

Aims

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.

Methods

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.

Results

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.

Conclusions

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.

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Authors and Affiliations

  1. Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy

    Giovanna Castoldi, Francesca Roma, Andrea Stella & Gianluca Perseghin

  2. Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Istituto di Anatomia Patologica, Sapienza Universita’ di Roma, Rome, Italy

    Cira R. T. di Gioia & Raffaella Carletti

  3. Dipartimento di Medicina Interna e Riabilitazione, Policlinico di Monza, Monza, Italy

    Giuseppina Manzoni & Gianluca Perseghin

  4. Unità Complicanze del Diabete, Diabetes Research Institute, Istituto Scientifico San Raffaele, Milan, Italy

    Gianpaolo Zerbini

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  1. Giovanna Castoldi
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Correspondence to Giovanna Castoldi.

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Ethical approval

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).

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Castoldi, G., di Gioia, C.R.T., Roma, F. et al. Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats. Acta Diabetol 56, 97–104 (2019). https://doi.org/10.1007/s00592-018-1220-1

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