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

Giovanna Castoldi | Zendy; Cira Di Gioia | Zendy; C. Bombardi | Zendy; Carla Perego | Zendy; Lucia Perego | Zendy; Massimiliano Mancini | Zendy; Martina Leopizzi | Zendy; B. Corradi | Zendy; Stefano Perlini | Zendy; Gianpaolo Zerbini | Zendy; Andréa Stella | Zendy

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

Author(s) -

Giovanna Castoldi,

Cira Di Gioia,

C. Bombardi,

Carla Perego,

Lucia Perego,

Massimiliano Mancini,

Martina Leopizzi,

B. Corradi,

Stefano Perlini,

Gianpaolo Zerbini,

Andréa Stella

Publication year - 2009

Publication title -

clinical science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.91

H-Index - 138

eISSN - 1470-8736

pISSN - 0143-5221

DOI - 10.1042/cs20090234

Subject(s) - ramipril , medicine , endocrinology , diabetes mellitus , diabetic cardiomyopathy , streptozotocin , insulin , myocardial fibrosis , diabetic nephropathy , ace inhibitor , cardiac fibrosis , fibrosis , angiotensin converting enzyme , cardiomyopathy , heart failure , blood pressure

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 x kg(-1 )of body weight x day(-1)). At 2 months after the onset of diabetes, Ac-SDKP (1 mg x kg(-1) of body weight x 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-beta1 (transforming growth factor-beta1) 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-beta1 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-beta1 and phospho-Smad2/3levels, and improves diastolic function. Taken together, these findings suggest that, by inhibiting theTGF-beta/Smad pathway, Ac-SDKP protects against the development of diabetic cardiomyopathy

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