Ac-SDKP Reverses Inflammation and Fibrosis in Rats With Heart Failure After Myocardial Infarction

Abstract

Abstract-Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI). N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4-to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7Ϯ0.9 to 15.0Ϯ0.7 g/mg and in the reversal group from 22.6Ϯ2. , PϽ0.01 (reversal). Ac-SDKP did not alter either blood pressure or left ventricular hypertrophy (LVH); however, it depressed systolic cardiac function in the prevention study while having no significant effect in the reversal group. We concluded that Ac-SDKP has an anti-inflammatory effect in HF that may contribute to its antifibrotic effect; however, this decrease in fibrosis without changes in LVH was not accompanied by an improvement in cardiac function. Key Words: rat Ⅲ myocardial infarction Ⅲ cardiac function Ⅲ collagen Ⅲ macrophages Ⅲ transforming growth factor-␤ N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4-to 5-fold by angiotensin-converting enzyme inhibitors. Ac-SDKP is released from its precursor thymosin-␤ 4 , which is present in most cells. 1 It inhibits pluripotent hematopoietic stem cell and hepatocyte proliferation by halting entry into the S phase of the cell cycle, maintaining cells in the G 0 /G 1 phase and thereby helping control their proliferation. [2][3][4] We have shown that in vitro Ac-SDKP inhibited cardiac fibroblast proliferation and collagen synthesis, 5 while in vivo it prevented collagen deposition in the left ventricle (LV) and kidneys in rats with aldosterone-salt hypertension and renovascular hypertension. 5,6 This decrease in collagen deposition was associated with a reduced number of proliferating cell nuclear antigen (PCNA)-positive cells, a marker of cell proliferation. These effects of Ac-SDKP occurred without changes in blood pressure or cardiomyocyte hypertrophy. Our studies suggest that one of the mechanisms by which Ac-SDKP prevents fibrosis is by inhibiting fibroblast proliferation and collagen synthesis. It is also known that inflammation plays a central role in the pathogenesis of interstitial and perivascular cardiac fibrosis in heart failure (HF) post-myocardial infarction (MI). Fibrosis is often co-localized with macrophages, which release cytokines such as transforming growth factor-␤ (TGF-␤) that play a crucial role in myocardial fibrosis. 7 There is evidence that Ac-SDKP inhibits TGF-␤ signal transduction through suppression of Smad2 phosphorylation. 8,9 However, it is not known whether it also inhibits the expression of TGF-␤.In the present study,...

N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal inflammation and tubulointerstitial fibrosis in rats

“…In previous in vivo studies, there is convincing evidence that Ac-SDKP, administered chronically in rat models of hyper- tension and myocardial infarction, prevented interstitial collagen deposition (4,16) by decreasing the interstitial cell proliferation, monocyte/macrophage infiltration and TGF-ß1 expression. Lin et al (17) reported that Ac-SDKP has an aortic antifibrotic effect due to a reduced expression of the profibrotic cytokine TGF-ß1 in the ANG II-induced hypertension rat model and that long-term Ac-SDKP treatment (18) and to suppress DNA and collagen synthesis in cardiac fibroblasts.…”

Thymosin β as an Actin-binding Protein with a Variety of Functions

“…Similar hopes are associated with Ac-SD-KP [19]. This peptide is so short that synthesizing it under laboratory conditions is relatively uncomplicated and not very expensive, which is an additional, unquestionable advantage.…”

“…On the other hand, the experimental data supports the thesis about the potential therapeutic properties of Tβ4 and derivatives of this peptide-sulfoxide and Ac-SDKP. These molecules are considered to be a potential factor applicable in the treatment of cardiovascular diseases, corneal and skin wounds and brain injuries [19,20,22,28]. Based on an understanding the numerous activities of Tβ4, it is postulated that the peptide will be used in the treatment of, inter alia, myocardial infarction, chronic heart failure, diabetes, lupus, stroke, multiple sclerosis, pressure ulcers, burns, dry eye, viral infections and septic shock [28].…”

“…by administration of captopril), Ac-SDKP concentration in the blood increases up to 5-fold [18]. It is credited with strong characteristics for inhibiting the expression of collagen and TGFβ (transforming growth factor β), limiting fibroblast proliferation, infiltration of macrophages, inhibiting the development of inflammation and accelerating neovascularization [18,19].…”

Establishing the Role of Angiotensin-Converting Enzyme in Renal Function and Blood Pressure Control through the Analysis of Genetically Modified Mice

“…Although angiotensin I is a good substrate for both of the two catalytic sites of ACE, other peptide substrates show distinct preferences for only one of the ACE catalytic sites. An example is the ACE substrate acetyl-SDKP that has been implicated as an antifibrotic and a bone marrow-suppressive peptide (14,15). Acetyl-SDKP is effectively hydrolyzed only by the N-terminal catalytic domain of ACE; ACE inhibition is associated with an elevation in blood levels of this peptide (16).…”