Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase

Wang, Ding; Yang, Xiao‐Ping; Liu, Yunhe; Carretero, Oscar A.; LaPointe, Margot C.

doi:10.1016/s0895-7061(98)00235-0

Cited by 74 publications

(51 citation statements)

References 31 publications

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“…However, the pathophysiological significance of iNOS induction in HF is not clear. We and others have shown that pharmacological inhibition of iNOS significantly reduced infarct size in rats with acute myocardial ischemia (38) and prevented cardiac dysfunction and heart failure post-MI (31). In the present study, we found that mice lacking iNOS had better preserved cardiac function and tended to have less severe chamber dilatation and myocyte hypertrophy post-MI.…”

Section: Effect Of Inos Deficiency On Cardiac Remodeling and Dysfunctsupporting

confidence: 68%

“…We and others have reported that selective inhibition of iNOS reduced infarct size in rats with acute coronary artery occlusion (38) and ameliorated cardiac dysfunction in strokeprone spontaneously hypertensive rats (1). Deletion of the iNOS gene attenuated endotoxin-induced myocardial dysfunction (36), VCAM-1 expression, and neointima formation in mice with arterial injury (6), while overexpression of iNOS in the heart resulted in a generation of OONO Ϫ , heart block, and sudden death (29).…”

mentioning

confidence: 95%

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Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

Liu

Carretero

Cingolani

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

107

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. Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 289: H2616-H2623, 2005. First published July 29, 2005 doi:10.1152/ajpheart.00546.2005.-Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS Ϫ/Ϫ ), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N -nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS Ϫ/Ϫ mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MIϩvehicle, and MIϩL-NAME (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS Ϫ/Ϫ compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS Ϫ/Ϫ mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.

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Section: Effect Of Inos Deficiency On Cardiac Remodeling and Dysfunctsupporting

confidence: 68%

mentioning

confidence: 95%

Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

Liu

Carretero

Cingolani

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

107

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“…21 In the rat, NOS2 mRNA expression in the infarcted region peaked 6 hours after coronary ligation and returned to baseline by 1 week. 22 Likewise, in the mouse, we found that NOS2 mRNA was increased in the infarct region at 3 days after MI, peaked at 7 days, and returned to baseline by 14 days. 23 NOS2-derived NO can cause myocyte apoptosis.…”

Section: Lack Of Effect On MI Sizesupporting

confidence: 57%

Mice Lacking Inducible Nitric Oxide Synthase Have Improved Left Ventricular Contractile Function and Reduced Apoptotic Cell Death Late After Myocardial Infarction

Sam

Sawyer

Xie

et al. 2001

Circulation Research

138

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Abstract-Nitric oxide produced by inducible nitric oxide synthase (NOS2) has been implicated in the pathophysiology of chronic myocardial remodeling and failure. We tested the role of NOS2 in left ventricular (LV) remodeling early (1 month) and late (4 months) after myocardial infarction (MI) in mice lacking NOS2. MI size measured 7 days, 1 month, and 4 months after MI was the same in NOS2 knockout (KO) and wild-type (WT) mice. The LV end-diastolic pressure-volume relationship measured by the isovolumic Langendorff technique showed a progressive rightward shift from 1 to 4 months after MI in WT mice. LV developed pressure measured over a range of LV volumes was reduced at 1 and 4 months after MI in WT mice (PϽ0.05 and PϽ0.01 versus shams, respectively). In KO mice, the rightward shift was similar to that in WT mice at 1 and 4 months after MI, as was peak LV developed pressure at 1 month after MI. In contrast, at 4 months after MI, peak LV developed pressure in KO mice was higher than in WT mice (PϽ0.05 versus WT) and similar to that in sham-operated mice. At 1 month after MI, the frequency of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive myocytes in the remote myocardium was increased to a similar extent in WT and KO mice. At 4 months after MI, the frequency of apoptotic myocytes was increased in WT mice but not in KO mice (PϽ0.05 versus WT). Improved contractile function and reduced apoptosis were associated with reduced mortality rate in KO mice at 4 months after MI. Thus, NOS2 does not play an important role in determining infarct size or early LV remodeling during the first month after MI. In contrast, during late (ie, 4 months after MI) remodeling, NOS2 in remote myocardium contributes to decreased contractile function, increased myocyte apoptosis in remote myocardium, and reduced survival. Key Words: myocardial remodeling Ⅲ nitric oxide synthase Ⅲ myocardial infarction Ⅲ mouse Ⅲ apoptosis N itric oxide (NO), alone or in combination with other reactive oxygen species, can depress myocyte contractile function, 1 attenuate myocyte hypertrophy, 2 and cause myocyte death 3,4 and/or apoptosis. 5,6 Both inducible nitric oxide synthase (NOS2) 7-9 and inflammatory cytokines that induce NOS2, such as tumor necrosis factor-␣ 10,11 may be increased chronically in failing myocardium. These observations have led to the thesis that expression of NOS2 in the myocardium contributes to abnormal function and pathological remodeling in chronic myocardial failure. 12 To test the role of NOS2 in chronic myocardial remodeling, transgenic mice lacking NOS2 were subjected to myocardial infarction (MI) by coronary ligation. 13 At 1 and 4 months after MI, left ventricular (LV) chamber volume and contractile function were assessed using the isovolumic (balloon-in-LV) Langendorff technique, and myocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method. Materials and Methods Experimental ModelNOS2 knockout (KO) mice in the F6 generation on a C57Bl6/...

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“…Furthermore, in the setting of brief ischemia followed by reperfusion, we are interested in whether the reduction in TTC-negative tissue observed in early reperfusion signifies genuine reduction of eventual infarct size following extended reperfusion. Because the stained myocardium consists of a complex mixture of necrotic and surviving myocytes in the early reperfusion, at that time the method of TTC staining has limitations in its accuracy for evaluation of cell necrosis (24); furthermore, inducible NO synthase (iNOS) induced by proinflammatory cytokines occurring during the late phase of postischemic infarction could increase infarct size (47)(48)(49).…”

mentioning

confidence: 99%

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

Fu¹,

Wang²,

Chen³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. Am J Physiol Heart Circ Physiol 293: H1545-H1552, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00064.2007.-In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), and NO-aspirin (56 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n ϭ 23), aspirin (n ϭ 22), and NO-aspirin groups (n ϭ 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 Ϯ 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin-and NOaspirin-pretreated groups, 36.7 Ϯ 1.8 and 22.9 Ϯ 4.3%, respectively (both P Ͻ 0.05 compared with vehicle group; P Ͻ 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemiareperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P Ͻ 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P Ͻ 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N G -nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion. nitroaspirin; aspirin; cardioprotection; ischemia-reperfusion; infarct size ISCHEMIC MYOCARDIAL TISSUE will inevitably induce necrosis if blood flow is not restored immediately. Early reperfusion after coronary obstruction is well established to recover injured myocardium; nevertheless, reperfusion itself is believed to bring about additional cellular injury (25,30). During the last two decades, numerous studies have been done that focus on the roles of nitric oxide (NO) in the pathogenesis progress and pharmacological intervention of myocardial ischemia and reperfusion. Of them, exogenous NO donors may provide therapeutic benefit and are also a recent conceptual advance in the management of reperfusion damage (1,17,19,39). However, conventional NO donors (e.g., organic nitrates) frequently result in unwanted hemodynamic effects due to the ...

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Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase

Cited by 74 publications

References 31 publications

Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

Mice Lacking Inducible Nitric Oxide Synthase Have Improved Left Ventricular Contractile Function and Reduced Apoptotic Cell Death Late After Myocardial Infarction

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

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