Chronic effects of losartan on the muscles and the serologic profiles of mdx mice

Lee, Eun-Mi; Kim, Dae-Yong; Kim, Ah-Young; Lee, Eunjoo; Kim, Sang-Hyeob; Lee, Myeong-Mi; Sung, Soo-Eun; Park, Jin‐Kyu; Jeong, Kyu‐Shik

doi:10.1016/j.lfs.2015.10.023

Cited by 27 publications

(29 citation statements)

References 24 publications

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“…Serum-based enzyme tests have been widely used for various applications in the clinic [ 33 – 35 ]. And a variety of serum enzymes, such as CK, ALT, and AST, were reported to increase in muscular dystrophy [ 36 , 37 ]. The elevation of serum enzymes in dystrophinopathy is thought to be due to their release from injured myofibers rather than to liver injury as indicated by liver biopsy in patients [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy

Wang

Chen

et al. 2018

Disease Markers

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Objective To investigate the ratios of creatine kinase (CK) to aminotransferases as biomarkers of acute liver injury in dystrophinopathy. Methods C57 and mdx (dystrophic) mice were treated with a hepatotoxic reagent D-galactosamine (D-GalN). The degrees of liver and muscle injury were assessed using histological examinations. To examine whether serum CK-adjusted aminotransferase levels could indicate liver status in dystrophic mice, the CK/alanine aminotransferase (ALT) and CK/aspartate aminotransferase (AST) ratios were analyzed. Furthermore, we enrolled 658 male patients with dystrophinopathy and 378 male patients without muscle and liver injury as control, whose serum ALT, AST, and CK levels were examined. Results Animal experiments indicated that D-GalN treatment could induce acute liver injury but not muscle injury. Additionally, D-GalN decreased the CK/ALT and CK/AST ratios in both C57 mice and mdx mice (P < 0.001). However, there was an overlap of the CK/AST ratio between dystrophic mice with and without acute liver injury. In patients with dystrophinopathy, CK-adjusted ALT diminished the variability associated with age, genotype, clinical phenotype, and motor function (P > 0.05). Conclusions CK/ALT is a potential biomarker for the differential evaluation of acute liver injury in dystrophic mice, which highlights the value to further evaluate the practice of CK/ALT in dystrophinopathy patients.

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Section: Discussionmentioning

confidence: 99%

Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy

Wang

Chen

et al. 2018

Disease Markers

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“…ACE inhibitors have been suggested to protect muscle function in older people, although more recent prospective studies did not confirm this association [23,24]. There is some experimental evidence that ARBs may be beneficial to muscle function in a deconditioned animal model [25,26]. However, the effect of ARB has not been reported in human muscle.…”

Section: Discussionmentioning

confidence: 99%

ARB users exhibit a lower fracture incidence than ACE inhibitor users among older hypertensive men

2016

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“…Multiple studies aimed at modulating the mdx phenotype have pointed to angiotensin-related signaling pathways and oxidative stress as important factors in both the skeletal and cardiac phenotype of dystrophic mice [26][27][28][29][30][31]. Importantly, drugs including ACE inhibitors (ACEi), angiotensin receptor blockers (ARBs), and antioxidants have shown a significant benefit for dystrophic mice and human patients [22,[32][33][34][35][36][37][38]. Current recommendations guide clinicians to consider initiating ACEi or ARB therapy at the age of 10 in Duchenne patients even without cardiac symptoms.…”

Section: Introductionmentioning

confidence: 99%

Acute AT1R blockade prevents isoproterenol-induced injury in mdx hearts

Meyers

Heitzman

Krebsbach

et al. 2019

Journal of Molecular and Cellular Cardiology

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Background: Duchenne muscular dystrophy (DMD) is an X-linked disease characterized by skeletal muscle degeneration and a significant cardiomyopathy secondary to cardiomyocyte damage and myocardial loss. The molecular basis of DMD lies in the absence of the protein dystrophin, which plays critical roles in mechanical membrane integrity and protein localization at the sarcolemma. A popular mouse model of DMD is the mdx mouse, which lacks dystrophin and displays mild cardiac and skeletal pathology that can be exacerbated to advance the disease state. In clinical and pre-clinical studies of DMD, angiotensin signaling pathways have emerged as therapeutic targets due to their adverse influence on muscle remodeling and oxidative stress. Here we aim to establish a physiologically relevant cardiac injury model in the mdx mouse, and determine whether acute blockade of the angiotensin II type 1 receptor (AT 1 R) may be utilized for prevention of dystrophic injury. Methods and Results: A single IP injection of isoproterenol (Iso, 10 mg/kg) was used to induce cardiac stress and injury in mdx and wild type (C57Bl/10) mice. Mice were euthanized 8 hours, 30 hours, 1 week, or 1 month following the injection, and hearts were harvested for injury evaluation. At 8 and 30 hours post-injury, mdx hearts showed 2.2-fold greater serum cTnI content and 3-fold more extensive injury than wild type hearts. Analysis of hearts 1 week and 1 month after injury revealed significantly higher fibrosis in mdx hearts, with a more robust and longerlasting immune response compared to wild type hearts. In the 30-hour group, losartan treatment initiated 1 hour before Iso injection protected dystrophic hearts from cardiac damage, reducing mdx acute injury area by 2.8-fold, without any significant effect on injury in wild type hearts. However, both wild type and dystrophic hearts showed a 2-fold reduction in the magnitude of the macrophage response to injury 30 hours after Iso with losartan.

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Chronic effects of losartan on the muscles and the serologic profiles of mdx mice

Cited by 27 publications

References 24 publications

Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy

Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy

ARB users exhibit a lower fracture incidence than ACE inhibitor users among older hypertensive men

Acute AT1R blockade prevents isoproterenol-induced injury in mdx hearts

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