Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats

Giovanna Castoldi, Cira R T di Gioia, Camila Bombardi, Carla Perego, Lucia Perego, Massimiliano Mancini, Martini Leopizzi, Barbara Gorradi, Stefano Perlini, Gianpaolo Zerbini, Andrea Stella

Research output: Contribution to journalArticlepeer-review

Abstract

Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is a physiological tetrapeptide hydrolysed by ACE (angiotensin-converting enzyme). In experimental models of hypertension, Ac-SDKP has antifibrotic effects in the heart; however, the role of Ac-SDKP in diabetic cardiomyopathy is currently unknown. The aim of the present study was to evaluate the effect of Ac-SDKP on cardiac systolic and diastolic function, and interstitial and perivascular fibrosis in the heart of diabetic rats. Diabetes was induced in 55 Sprague - Dawley rats by streptozotocin injection. Control rats (n=18) underwent only buffer injection. Out of the 55 diabetic rats, 19 were chronically treated with insulin and 13 with the ACEI (ACE inhibitor) ramipril (3 mg · kg-1 of body weight · day-1). At 2 months after the onset of diabetes, Ac-SDKP (1 mg · kg-1 of body weight · day-1) was administered by osmotic minipumps for 8 weeks to eight control rats, 13 diabetic rats, seven diabetic rats treated with ramipril and nine insulin-treated diabetic rats. Diabetic rats had a significant increase in blood glucose levels. Left ventricular interstitial and perivascular fibrosis, and TGF-β1 (transforming growth factor-β1) protein levels were increased in diabetic rats, but not in insulin-treated diabetic rats and ramipril-treated diabetic rats, compared with control rats. Ac-SDKP administration significantly reduced left ventricular interstitial and perivascular fibrosis in diabetic rats and in diabetic rats treated with ramipril. This was accompanied by a significant reduction in active TGF-β1 and phospho-Smad2/3 protein levels in myocardial tissue of diabetic rats. Echocardiography showed that diabetes was associated with increased end-systolic diameters, and depressed global systolic function and diastolic dysfunction, as assessed by transmitral Doppler velocity profile. These changes were completely reversed by insulin or ramipril treatment. Ac-SDKP treatment partially restored diastolic function in diabetic rats. In conclusion, Ac-SDKP administration in diabetic rats reduces left ventricular interstitial and perivascular fibrosis, active TGF-β1 and phospho-Smad2/3 levels, and improves diastolic function. Taken together, these findings suggest that, by inhibiting the TGF-β/Smad pathway, Ac-SDKP protects against the development of diabetic cardiomyopathy.

Original languageEnglish
Pages (from-to)211-220
Number of pages10
JournalClinical Science
Volume118
Issue number3
DOIs
Publication statusPublished - 2010

Keywords

  • Angiotensin-converting enzyme inhibitor (ACEI)
  • Diabetic cardiomyopathy
  • Echocardiography
  • Fibrosis
  • N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)
  • Smad
  • Transforming growth factor-β1 (TGF-β1)

ASJC Scopus subject areas

  • Medicine(all)

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