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