Abstract:
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 (AT1R) 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 h, 30 h, 1 week, or 1 month following the injection, and hearts were harvested for injury evaluation. At 8 and 30 h 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 longer-lasting immune response compared to wild type hearts. In the 30-hour group, losartan treatment initiated 1 h 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 h after Iso with losartan. CONCLUSIONS:This work demonstrates that acute blockade of AT1R has the potential for robust injury prevention in a model of Iso-induced dystrophic heart injury. In addition to selectively limiting dystrophic cardiac damage, blocking AT1R may serve to limit the inflammatory nature of the immune response to injury in all hearts. Our findings strongly suggest that earlier adoption of angiotensin receptor blockers in DMD patients could limit myocardial damage and subsequent cardiomyopathy.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Meyers TA,Heitzman JA,Krebsbach AM,Aufdembrink LM,Hughes R,Bartolomucci A,Townsend Ddoi
10.1016/j.yjmcc.2019.01.013subject
Has Abstractpub_date
2019-03-01 00:00:00pages
51-61eissn
0022-2828issn
1095-8584pii
S0022-2828(18)31260-4journal_volume
128pub_type
杂志文章abstract::Short duration exposure to cellular stresses have been shown to activate p38 mitogen-activated protein kinase (MAPK) in cultured rat ventricular cardiomyocytes and isolated perfused hearts; however, effects of chronic stress on p38 MAPK are not well understood. This study determined whether alterations in the p38 MAPK...
journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
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更新日期:2012-04-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2013.07.018
更新日期:2013-10-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of molecular and cellular cardiology
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更新日期:2014-09-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(95)92019-6
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章,评审
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(88)80146-9
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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更新日期:2012-03-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2017.06.003
更新日期:2017-07-01 00:00:00
abstract::Monoclonal antibodies (MAb) to myosin heavy chains were prepared from one adult human ventricular myocardium. Several of these MAb reacted by indirect immunofluorescence in a heterogenous way on cryostat transverse sections of fibers from human atrial myocardium, suggesting the presence of different forms of myosin wi...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(85)80037-7
更新日期:1985-08-01 00:00:00
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2010.02.009
更新日期:2010-06-01 00:00:00
abstract::Lack of endothelial nitric oxide synthase (eNOS) may affect the sensitivity of cyclic GMP signaling through soluble guanylyl cyclase (sGC). We hypothesized that in eNOS knockout (eNOS-/-) mice, stimulation of guanylyl cyclase would have enhanced effects inhibiting cardiac contraction. We measured cell shortening and c...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2005.08.008
更新日期:2005-12-01 00:00:00
abstract:RATIONALE:Truncation mutations in the MYBPC3 gene, encoding for cardiac myosin-binding protein C (MyBP-C), are the leading cause of hypertrophic cardiomyopathy (HCM). Whole heart, fiber and molecular studies demonstrate that MyBP-C is a potent modulator of cardiac contractility, but how these mutations contribute to HC...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2018.12.003
更新日期:2019-02-01 00:00:00