Long-Term Effect of N -Acetyl-Seryl-Aspartyl-Lysyl-Proline on Left Ventricular Collagen Deposition in Rats With 2-Kidney, 1-Clip Hypertension

Abstract

Background-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation. Ac-SDKP plasma concentration is increased 5-fold after angiotensin-converting enzyme inhibition. Here we studied the effect of Ac-SDKP on monocyte/macrophage infiltration, fibroblast proliferation, and collagen deposition in the rat heart in renovascular hypertension. Methods and Results-We investigated whether long-term Ac-SDKP administration would prevent left ventricular (LV) hypertrophy and interstitial collagen deposition in rats with 2-kidney, 1-clip (2K-1C) hypertension. Ac-SDKP (400 g · kg Ϫ1 · d Ϫ1 ) did not affect development of hypertension. Mean blood pressure was similar in rats with 2K-1C hypertension whether they were given vehicle or Ac-SDKP and was higher than in controls. Both LV weight and cardiomyocyte size were significantly increased in rats with 2K-1C hypertension compared with controls and were unaffected by Ac-SDKP. Proliferating cell nuclear antigen-and monocyte/macrophage-positive cells were increased in the LV of 2K-1C hypertensive rats; this increase was significantly blunted by Ac-SDKP (PϽ0.001). LV interstitial collagen fraction was also increased in 2K-1C hypertensive rats given vehicle (10.1Ϯ0.8%) compared with sham (5.3Ϯ0.1%, PϽ0.0001), and this increase was prevented by Ac-SDKP (5.4Ϯ0.4%, PϽ0.001). Conclusions-Ac-SDKP inhibited monocyte/macrophage infiltration, cell proliferation, and collagen deposition in the LV of hypertensive rats without affecting blood pressure or cardiac hypertrophy, suggesting that it may be partly responsible for the cardioprotective effect of angiotensin-converting enzyme inhibitors.

Ac-SDKP Reverses Cardiac Fibrosis in Rats With Renovascular Hypertension

“…For this, we examined the pressor and depressor response to Ang I and bradykinin (BK), respectively, in an additional group of rats treated with various doses of Ac-SDKP. Since we previously found that cardiac fibrosis is fully established 8 weeks after induction of 2K-1C hypertension, 10 in the present study Ac-SDKP was started at the end of week 8 and continued for 8 weeks.…”

“…10,11 In the present study, we tested whether Ac-SDKP can reverse cardiac fibrosis in 2K-1C hypertensive rats. We found that LV collagen deposition was significantly increased at 8 weeks after clipping and remained elevated at 16 weeks compared with sham-clipped rats, as assessed by hydroxyproline assay and histochemical analysis.…”

“…Hypertension was induced by clipping the left renal artery as described previously. 10 Ac-SDKP (obtained from Dr Domenico Regoli, University of Sherbrooke, Canada) at 400 or 800 g/kg per day was started 8 weeks after clipping and continued for 8 weeks. Ac-SDKP was infused subcutaneously through an osmotic minipump (Alzet).…”

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Inhibits TGF-β–Mediated Plasminogen Activator Inhibitor-1 Expression via Inhibition of Smad Pathway in Human Mesangial Cells

“…Ac-SDKP was shown to suppress the proliferation of renal fibroblasts (14) and to inhibit DNA synthesis as well as collagen deposition in cardiac fibroblasts (15). In a hypertensive rat model, long-term administration of Ac-SDKP can ameliorate renal fibrosis and ventricular hypertrophy (16,17). These observations suggest that the reno-protective effect of ACE-I could be partly mediated by the accumulation of Ac-SDKP in the plasma.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…137 AcSDKP restored glomerular sclerosis and renal fibrosis in hypertensive rat models and diabetic and non-diabetic kidney disease models without altering blood pressure. 138,139 The incubation of human mesangial cells in the presence of AcSDKP leads to the cytoplasmic mobilization of smad7 in the absence of TGFb stimulation. 140 The smad7 level increases in vivo following AcSDKP administration, supporting the smad7 mediated anti-TGF-b effects of AcSDKP.…”