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. © The Authors Journal compilation © 2010 Biochemical Society.

Castoldi, G., Di Gioia, C., Bombardi, C., Perego, C., Perego, L., Mancini, M., et al. (2010). Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. CLINICAL SCIENCE, 118(3), 211-220 [10.1042/CS20090234].

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

CASTOLDI, GIOVANNA
;
STELLA, ANDREA
2010

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. © The Authors Journal compilation © 2010 Biochemical Society.
Articolo in rivista - Articolo scientifico
Scientifica
Angiotensin-converting enzyme inhibitor (ACEI); Diabetic cardiomyopathy; Echocardiography; Fibrosis; N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP); Smad; Transforming growth factor-β1 (TGF-β1);
English
Castoldi, G., Di Gioia, C., Bombardi, C., Perego, C., Perego, L., Mancini, M., et al. (2010). Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. CLINICAL SCIENCE, 118(3), 211-220 [10.1042/CS20090234].
Castoldi, G; Di Gioia, C; Bombardi, C; Perego, C; Perego, L; Mancini, M; Leopizzi, M; Corradi, B; Perlini, S; Zerbini, G; Stella, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/22666
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