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Published on: May 4, 2015
Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms
Sei Nakata1, Masato Tsutsui, Hiroaki Shimokawa
1Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Background:
The roles of nitric oxide (NO) in the cardiovascular system have been investigated extensively in pharmacological studies with NO synthase (NOS) inhibitors and in studies with NOS isoform-deficient mice. However, because of the nonspecificity of the NOS inhibitors and the compensatory interactions among NOS isoforms (nNOS, iNOS, and eNOS), the ultimate roles of endogenous NO derived from the entire NOS system are still poorly understood. In this study, we examined this point in mice deficient in all 3 NOS isoforms (triply n/i/eNOS(-/-) mice) that we have recently developed.
Methods And Results:
The triply n/i/eNOS(-/-) mice, but not singly eNOS(-/-) mice, exhibited markedly reduced survival, possibly due to spontaneous myocardial infarction accompanied by severe coronary arteriosclerotic lesions. Furthermore, the triply n/i/eNOS(-/-) mice manifested phenotypes that resembled metabolic syndrome in humans, including visceral obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance. Importantly, activation of the renin-angiotensin system was noted in the triply n/i/eNOS(-/-) mice, and long-term oral treatment with an angiotensin II type 1 receptor blocker significantly suppressed coronary arteriosclerotic lesion formation and the occurrence of spontaneous myocardial infarction and improved the prognosis of those mice, along with ameliorating the metabolic abnormalities.
Conclusions:
These results provide the first direct evidence that genetic disruption of the whole NOS system causes spontaneous myocardial infarction associated with multiple cardiovascular risk factors of metabolic origin in mice in vivo through the angiotensin II type 1 receptor pathway, demonstrating the critical role of the endogenous NOS system in maintaining cardiovascular and metabolic homeostasis.
Insights
Mice lacking all nitric oxide synthase (NOS) enzymes developed spontaneous heart attacks and metabolic syndrome. Blocking the angiotensin II type 1 receptor improved survival and metabolic health, highlighting the NOS system's importance.
Area of Science:
- Cardiovascular Science
- Metabolic Science
- Physiology
Background:
- Nitric oxide (NO) roles in cardiovascular health are complex due to NOS isoform interactions.
- Previous studies using inhibitors or single-gene knockout mice had limitations in understanding the overall NO system's function.
- The development of triple nitric oxide synthase knockout (n/i/eNOS(-/-)) mice allows for a comprehensive investigation.
Purpose of the Study:
- To investigate the physiological roles of the entire endogenous nitric oxide synthase (NOS) system.
- To determine the consequences of lacking all three NOS isoforms (neuronal, inducible, and endothelial) in vivo.
- To explore the potential involvement of the renin-angiotensin system in the observed phenotypes.
Main Methods:
- Generation and characterization of triple n/i/eNOS(-/-) knockout mice.
- Assessment of survival rates, cardiac pathology (myocardial infarction, coronary arteriosclerosis), and metabolic parameters (obesity, hypertension, dyslipidemia, glucose intolerance).
- Pharmacological intervention using an angiotensin II type 1 receptor blocker.
Main Results:
- Triple n/i/eNOS(-/-) mice showed significantly reduced survival compared to single eNOS(-/-) mice, linked to myocardial infarction and severe coronary arteriosclerosis.
- These mice exhibited metabolic syndrome-like features: visceral obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance.
- Activation of the renin-angiotensin system was observed, and treatment with an angiotensin II type 1 receptor blocker ameliorated cardiovascular and metabolic abnormalities and improved prognosis.
Conclusions:
- Genetic ablation of the entire NOS system in mice leads to spontaneous myocardial infarction and cardiovascular risk factors of metabolic origin.
- The angiotensin II type 1 receptor pathway is implicated in the pathogenesis of these conditions.
- This study provides direct evidence for the critical role of the endogenous NOS system in maintaining cardiovascular and metabolic homeostasis.
