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

2019 ◽  
Vol 97 (8) ◽  
pp. 753-765
Author(s):  
Hongmei Peng ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Kamal M. Kassem ◽  
Imane A. Rhaleb ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Capillary Density ◽  
Cardiac Rupture ◽  
Gelatinolytic Activity ◽  
Intercellular Adhesion Molecule ◽  
P53 Expression ◽  
And Function

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.

scholarly journals Thymosin-β4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction

2014 ◽  
Vol 307 (5) ◽  
pp. H741-H751 ◽  
Author(s):  
Hongmei Peng ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Xiangguo Dai ◽  
Edward L. Peterson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cell Survival ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiac Rupture ◽  
Gelatinolytic Activity ◽  
P53 Expression

Thymosin-β4 (Tβ4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg·kg−1·day−1 ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tβ4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

scholarly journals Endoplasmic Reticulum Stress is Involved in DFMO Attenuating Isoproterenol-Induced Cardiac Hypertrophy in Rats

2016 ◽  
Vol 38 (4) ◽  
pp. 1553-1562 ◽  
Author(s):  
Yan Lin ◽  
Xiaojie Zhang ◽  
Wei Xiao ◽  
Bo Li ◽  
Jun Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cardiac Fibrosis ◽  
Regulation Of Gene Expression ◽  
Tunel Staining

Background/Aims: Studies performed in experimental animals have shown that polyamines contribute to several physiological and pathological processes, including cardiac hypertrophy. This involves an increase in ornithine decarboxylase (ODC) activity and intracellular polyamines associated with regulation of gene expression. Difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, has attracted considerable interest for its antiproliferative role, which it exerts through inhibition of the polyamine pathway and cell turnover. Whether DFMO attenuates cardiac hypertrophy through endoplasmic reticulum stress (ERS) is unclear. Methods: Myocardial hypertrophy was simulated by isoproterenol (ISO). Polyamine depletion was achieved using DFMO. Hypertrophy was estimated using the heart/body index and atrial natriuretic peptide (ANP) gene expression. Cardiac fibrosis and apoptosis were measured by Masson and TUNEL staining. Expression of ODC and spermidine/spermine N1-acetyltransferase (SSAT) were analyzed via real-time PCR and Western blot analysis. Protein expression of ERS and apoptosis factors were analyzed using Western blot analysis. Results: DFMO treatments significantly attenuated hypertrophy and apoptosis induced by ISO in cardiomyocytes. DFMO down-regulated the expression of ODC, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and Bax and up-regulated the expression of SSAT and Bcl-2. Finally, these changes were partially reversed by the addition of exogenous putrescine. Conclusion: The data presented here suggest that polyamine depletion could inhibit cardiac hypertrophy and apoptosis, which is closely related to the ERS pathway.

Inhibition of Cardiac Remodeling by Pravastatin Is Associated with Amelioration of Endoplasmic Reticulum Stress

2008 ◽  
Vol 31 (10) ◽  
pp. 1977-1987 ◽  
Author(s):  
Hui Zhao ◽  
Yulin Liao ◽  
Tetsuo Minamino ◽  
Yoshihiro Asano ◽  
Masanori Asakura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cardiac Remodeling

scholarly journals Localization and function in endoplasmic reticulum stress tolerance of ERdj3, a new member of Hsp40 family protein

2004 ◽  
Vol 9 (3) ◽  
pp. 253 ◽  
Author(s):  
Katsuya Nakanishi ◽  
Kenjiro Kamiguchi ◽  
Toshihiko Torigoe ◽  
Chika Nabeta ◽  
Yoshihiko Hirohashi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Stress Tolerance ◽  
Family Protein ◽  
And Function

scholarly journals Effects of Methotrexate on Plasma Cytokines and Cardiac Remodeling and Function in Postmyocarditis Rats

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Zhengang Zhang ◽  
Pei Zhao ◽  
Aihua Li ◽  
Xiaolei Lv ◽  
Yang Gao ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Low Dose ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Tnf Alpha ◽  
Type I ◽  
Autoimmune Myocarditis ◽  
Dose Methotrexate ◽  
And Function

Excessive immune activation and inflammatory mediators may play a critical role in the pathogenesis of chronic heart failure. Methotrexate is a commonly used anti-inflammatory and immunosuppressive drug. In this study, we used a rat model of cardiac myosin-induced experimental autoimmune myocarditis to investigate the effects of low-dose methotrexate (0.1 mg/kg/d for 30 d) on the plasma level of cytokines and cardiac remodeling and function. Our study showed that levels of tumor necrosis factor-(TNF-)alpha and interleukin-6 (IL-6) are significantly increased in postmyocarditis rats, compared with the control rats. Methotrexate treatment reduced the plasma levels of TNF-alpha and IL-6 and increased IL-10 level, compared to saline treatment. In addition, postmyocarditis rats showed significant cardiac fibrosis characterized by increased myocardial collagen volume fraction, perivascular collagen area, and the ratio of collagen type I to type III, compared with the control rats. However, MTX treatment not only markedly attenuated cardiac fibrosis, diminished the left ventricular end-diastolic dimension, but also increased the left ventricular ejection fraction and fractional shortening. Collectively, these results suggest that low-dose methotrexate has ability to regulate inflammatory responses and improves cardiac function and hence contributes to prevent the development of postmyocarditis dilated cardiomyopathy.

scholarly journals Human Genetic Disorders Resulting in Systemic Selenoprotein Deficiency

2021 ◽  
Vol 22 (23) ◽  
pp. 12927
Author(s):  
Erik Schoenmakers ◽  
Krishna Chatterjee
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Genetic Disorders ◽  
Cerebral Atrophy ◽  
Serum Selenium ◽  
Neurological Phenotype ◽  
Serum Selenium Levels ◽  
Ongoing Surveillance ◽  
And Function ◽  
Human Genetic Disorders

Selenium, a trace element fundamental to human health, is incorporated as the amino acid selenocysteine (Sec) into more than 25 proteins, referred to as selenoproteins. Human mutations in SECISBP2, SEPSECS and TRU-TCA1-1, three genes essential in the selenocysteine incorporation pathway, affect the expression of most if not all selenoproteins. Systemic selenoprotein deficiency results in a complex, multifactorial disorder, reflecting loss of selenoprotein function in specific tissues and/or long-term impaired selenoenzyme-mediated defence against oxidative and endoplasmic reticulum stress. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Selenoprotein deficiency due to SECISBP2 and TRU-TCA1-1 defects are characterized by abnormal circulating thyroid hormones due to lack of Sec-containing deiodinases, low serum selenium levels (low SELENOP, GPX3), with additional features (myopathy due to low SELENON; photosensitivity, hearing loss, increased adipose mass and function due to reduced antioxidant and endoplasmic reticulum stress defence) in SECISBP2 cases. Antioxidant therapy ameliorates oxidative damage in cells and tissues of patients, but its longer term benefits remain undefined. Ongoing surveillance of patients enables ascertainment of additional phenotypes which may provide further insights into the role of selenoproteins in human biological processes.

scholarly journals Intermittent Hypoxia Triggers Early Cardiac Remodeling and Contractile Dysfunction in the Time‐Course of Ischemic Cardiomyopathy in Rats

2020 ◽  
Vol 9 (16) ◽  
Author(s):  
Guillaume Bourdier ◽  
Maximin Détrait ◽  
Sophie Bouyon ◽  
Emeline Lemarié ◽  
Sandrine Brasseur ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cardiac Remodeling ◽  
Ischemic Cardiomyopathy ◽  
Sleep Disordered Breathing ◽  
Time Course ◽  
Hypoxia Inducible Factor ◽  
Contractile Dysfunction ◽  
Disordered Breathing

BACKGROUND Sleep‐disordered breathing is associated with a poor prognosis (mortality) in patients with ischemic cardiomyopathy. The understanding of mechanisms linking intermittent hypoxia (IH), the key feature of sleep‐disordered breathing, to ischemic cardiomyopathy progression is crucial for identifying specific actionable therapeutic targets. The aims of the present study were (1) to evaluate the impact of IH on the time course evolution of cardiac remodeling and contractile dysfunction in a rat model of ischemic cardiomyopathy; and (2) to determine the impact of IH on sympathetic activity, hypoxia inducible factor‐1 activation, and endoplasmic reticulum stress in the time course of ischemic cardiomyopathy progression. METHODS AND RESULTS Ischemic cardiomyopathy was induced by a permanent ligature of the left coronary artery in male Wistar rats (rats with myocardial infarction). Rats with myocardial infarction were then exposed to either IH or normoxia for up to 12 weeks. Cardiac remodeling and function were analyzed by Sirius red and wheat germ agglutinin staining, ultrasonography, and cardiac catheterization. Sympathetic activity was evaluated by spectral analysis of blood pressure variability. Hypoxia‐inducible factor‐1α activation and burden of endoplasmic reticulum stress were characterized by Western blots. Long‐term IH exposure precipitated cardiac remodeling (hypertrophy and interstitial fibrosis) and contractile dysfunction during the time course evolution of ischemic cardiomyopathy in rodents. Among associated mechanisms, we identified the early occurrence and persistence of sympathetic activation, associated with sustained hypoxia‐inducible factor‐1α expression and a delayed pro‐apoptotic endoplasmic reticulum stress. CONCLUSIONS Our data provide the demonstration of the deleterious impact of IH on post–myocardial infarction remodeling and contractile dysfunction. Further studies are needed to evaluate whether targeting sympathetic nervous system or HIF‐1 overactivities could limit these effects and improve management of coexisting ischemic cardiomyopathy and sleep‐disordered breathing.

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