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Nitric oxide depresses connexin 43 after myocardial infarction in mice
P E M Jackson1, Q P Feng, D L Jones
1Department of Physiology, University of Western Ontario, London, ON, Canada.
Insights
Increased nitric oxide (NO) from inducible nitric oxide synthase (iNOS) worsens heart failure by reducing cardiac connexin 43 (Cx43) levels and impairing heart function. This study investigated the iNOS-Cx43 link in mouse models of myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cardiac Pathophysiology
Background:
- Heart failure (HF) is a significant cause of mortality and morbidity.
- Reduced cardiac connexin 43 (Cx43) is observed in failing hearts, but its regulators are unknown.
- High nitric oxide (NO) levels, induced by inducible nitric oxide synthase (iNOS), are implicated in HF-related apoptosis and dysfunction.
Purpose of the Study:
- To investigate the relationship between inducible nitric oxide synthase (iNOS) and connexin 43 (Cx43) in the context of myocardial infarction (MI).
- To determine the impact of iNOS-derived NO on cardiac function and Cx43 expression post-MI.
Main Methods:
- Myocardial infarction was induced in wild-type and iNOS knockout mice.
- Cardiac function was assessed using left ventricular catheterization.
- Myocardial Cx43 and Cx45 protein levels were quantified via immunofluorescence and Western blotting.
- Primary cardiomyocyte cultures were used to assess the direct effect of NO on Cx43 expression.
Main Results:
- Mice lacking iNOS exhibited improved hemodynamic performance and reduced mortality after MI compared to wild-type mice.
- Myocardial Cx43 content was significantly reduced in wild-type mice post-MI, with a less pronounced reduction in iNOS knockout mice.
- In vitro, NO donors decreased Cx43 levels in cultured cardiomyocytes in a dose-dependent manner.
Conclusions:
- Increased NO production by iNOS exacerbates cardiac dysfunction and contributes to decreased myocardial Cx43 content following myocardial infarction.
- Targeting iNOS or NO signaling may represent a therapeutic strategy for heart failure.
Aims:
Heart failure (HF) is a major cause of death and morbidity. Connexin 43 (Cx43) content is reduced in the failing myocardium, but regulating factors have not been identified. In HF, inducible nitric oxide synthase (iNOS)-induced high levels of nitric oxide (NO) cause apoptosis and cardiac dysfunction. However, a direct iNOS-Cx43 link has not been demonstrated. We investigated this relationship in mice after myocardial infarction.
Methods:
Effects of myocardial infarction were evaluated 2 weeks after coronary artery ligation in wild-type C57BL/6 (WT) and iNOS(-/-) knockout mice. Myocardial Cx43 and Cx45 content were assessed by immunofluorescence confocal imaging and western blotting. Cardiac function was evaluated in anaesthetized mice using a micro pressure-tipped catheter inserted into the left ventricle.
Results:
Despite similar infarct size, deficiency in iNOS resulted in significantly lower plasma nitrate/nitrite levels, better haemodynamic performance and lower mortality 2 weeks after coronary ligation. Myocardial Cx43, but not Cx45, content was lower in WT mice following ligation. The reduction in Cx43 was less in iNOS(-/-) compared with WT mice. To assess the direct effect of NO on Cx43 expression, cultured neonatal mouse cardiomyocytes were employed. Incubation with the NO donor, S-nitroso-N-acetylpenicillamine, elicited a dose-dependent decrease in Cx43 content in cultured neonatal cardiomyocytes.
Conclusions:
Increased NO production from iNOS depressed cardiac performance and contributed to the decreased myocardial Cx43 content 2 weeks after myocardial infarction.
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