N-acetyl-seryl-aspartyl-lysyl-proline treatment protects heart against excessive myocardial injury and heart failure in mice

Abstract

Myocardial infarction (MI) in mice results in cardiac rupture at 4–7 days after MI, whereas cardiac fibrosis and dysfunction occur later. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic, and pro-angiogenic properties. We hypothesized that Ac-SDKP reduces cardiac rupture and adverse cardiac remodeling, and improves function by promoting angiogenesis and inhibiting detrimental reactive fibrosis and inflammation after MI. C57BL/6J mice were subjected to MI and treated with Ac-SDKP (1.6 mg/kg per day) for 1 or 5 weeks. We analyzed (1) intercellular adhesion molecule-1 (ICAM-1) expression; (2) inflammatory cell infiltration and angiogenesis; (3) gelatinolytic activity; (4) incidence of cardiac rupture; (5) p53, the endoplasmic reticulum stress marker CCAAT/enhancer binding protein homology protein (CHOP), and cardiomyocyte apoptosis; (6) sarcoplasmic reticulum Ca2+ ATPase (SERCA2) expression; (7) interstitial collagen fraction and capillary density; and (8) cardiac remodeling and function. Acutely, Ac-SDKP reduced cardiac rupture, decreased ICAM-1 expression and the number of infiltrating macrophages, decreased gelatinolytic activity, p53 expression, and myocyte apoptosis, but increased capillary density in the infarction border. Chronically, Ac-SDKP improved cardiac structures and function, reduced CHOP expression and interstitial collagen fraction, and preserved myocardium SERCA2 expression. Thus, Ac-SDKP decreased cardiac rupture, ameliorated adverse cardiac remodeling, and improved cardiac function after MI, likely through preserved SERCA2 expression and inhibition of endoplasmic reticulum stress.

Tβ4–Ac-SDKP pathway: Any relevance for the cardiovascular system?

“…We have also reported that T4, at a dose that is unable to generate optimal circulating Ac-SDKP concentrations (Rhaleb et al 2001 b ), prevents cardiac rupture and improves cardiac function post-myocardial infarction (MI) via its anti-inflammatory, proangiogenic, and anti-apoptotic actions in a murine model of acute MI (Peng et al 2014). Comparable results are obtained when Ac-SDKP was used instead of Tβ4 (Peng et al 2019, in press). The MI model in rodents shares both clinical and pathological features of post-MI with changes found in human hearts, including cardiac rupture and dysfunction (Bock-Marquette et al 2004).…”

Atractylenolide III Attenuates Apoptosis in H9c2 Cells by Inhibiting Endoplasmic Reticulum Stress through the GRP78/PERK/CHOP Signaling Pathway

“…TCM is widely applied in the prophylaxis and therapy of HF [24]. LGZGD, as one of the widely used TCM, can effectively regulate the cardiac function and structure in HF by ameliorating the microstructural remodeling, reducing the myocardial inflammation injury and myocardial fibrosis [9,10,[25][26][27], and can protect myocardial cells by inhibiting apoptosis of H9c2 cells [12]. As one of the active components of LGZGD, previous studies show that ATL-III has a protective effect on myocardial cells [20].…”

“…Persistent and severe ERS induces myocardial cell apoptosis, which is one mechanism responsible for the pathogenesis of HF [ 7 , 8 ]. As a result, suppression of ERS could be a major concern for HF [ 9 ].…”

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

“…An extensive body of literature has shown that C/EBPζ is involved in cardiomyocyte apoptosis, cardiac hypertrophy, and heart fibrosis. Various stimuli such as TAC, myocardial infraction (MI), and diabetes activate ER stress by increasing C/EBPζ expression in myocardial fibrosis [308][309][310]. In addition, C/EBPζ knockout mice display decreased cardiomyocyte apoptosis and subdued cardiac fibrosis under TAC, ischemia-reperfusion (I/R) injury, and Ang II-induced hypertension compared to wild-type mice [311][312][313].…”