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En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Published on: February 25, 2016
Functional nitric oxide synthase mislocalization in cardiomyopathy
Ahlke Heydemann1, Jill M Huber, Rahul Kakkar
1Department of Medicine, Section of Cardiology, The University of Chicago, 5841 S. Maryland, MC6088, Rm G611, Chicago, IL 60637, USA.
Abstract:
Mutations in the dystrophin glycoprotein complex, and in particular the sarcoglycan subcomplex, lead to cardiomyopathy and muscular dystrophy. Mice with mutations in gamma-sarcoglycan or delta-sarcoglycan develop cardiomyopathy that is characterized by focal regions of tissue damage. These focally damaged regions constitute 0-5% of cardiac tissue. In cardiomyopathy arising from sarcoglycan mutations, we found that endothelial nitric oxide synthase (eNOS) was significantly increased in focally damaged cardiac myocytes. In addition, we noted that nitric oxide (NO) was also increased in regions of tissue damage and altered membrane permeability. In sarcoglycan mutant mice, regionally increased cardiac NO was associated with hypersensitivity to carbachol and decreased sensitivity to adrenergic stimulation. Inhibition of NO production in sarcoglycan mutant mice was associated with improved recovery after carbachol and isoproterenol infusion. These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients.
Insights
Mutations in sarcoglycans cause heart damage and muscular dystrophy. Inhibiting nitric oxide synthase (NOS) improved cardiac function in mutant mice by correcting abnormal nitric oxide (NO) levels.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Molecular Genetics
Background:
- Dystrophin glycoprotein complex mutations, particularly in sarcoglycans, are linked to cardiomyopathy and muscular dystrophy.
- Sarcoglycan mutations in mice result in focal cardiac tissue damage and altered cellular function.
Purpose of the Study:
- To investigate the role of nitric oxide (NO) in sarcoglycan-deficient cardiomyopathy.
- To determine if modulating NO production can ameliorate cardiac dysfunction in these models.
Main Methods:
- Utilized mouse models with gamma-sarcoglycan or delta-sarcoglycan mutations.
- Measured endothelial nitric oxide synthase (eNOS) and NO levels in cardiac tissue.
- Assessed cardiac function through carbachol and isoproterenol stimulation.
- Evaluated the effects of nitric oxide synthase inhibition on cardiac recovery.
Main Results:
- Increased eNOS and NO were observed in focally damaged cardiac myocytes of mutant mice.
- Regional NO elevation correlated with hypersensitivity to carbachol and reduced adrenergic response.
- Inhibition of NO production improved cardiac recovery following pharmacological stimulation.
Conclusions:
- Focal cardiac damage in sarcoglycan mutant mice creates pathological NO gradients.
- Modulating NO production via NOS inhibition offers a therapeutic strategy for sarcoglycanopathies.
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