Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms.
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.


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.
Nakata
Sei
S
Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Tsutsui
Masato
M
Shimokawa
Hiroaki
H
Suda
Osamu
O
Morishita
Tsuyoshi
T
Shibata
Kiyoko
K
Yatera
Yasuko
Y
Sabanai
Ken
K
Tanimoto
Akihide
A
Nagasaki
Machiko
M
Tasaki
Hiromi
H
Sasaguri
Yasuyuki
Y
Nakashima
Yasuhide
Y
Otsuji
Yutaka
Y
Yanagihara
Nobuyuki
N
D052242:Adiponectin / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D050171:Dyslipidemias / Q000453:epidemiology; D018149:Glucose Intolerance / Q000453:epidemiology; D006706:Homeostasis; D006973:Hypertension / Q000453:epidemiology; D050152:Intra-Abdominal Fat; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D009765:Obesity / Q000453:epidemiology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D012307:Risk Factors; D016019:Survival Analysis
D052242:Adiponectin; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse