(Hypertension. 1999;34:24-30.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Endothelial Nitric Oxide Gene Knockout Mice
Cardiac Phenotypes and the Effect of Angiotensin-Converting Enzyme Inhibitor on Myocardial Ischemia/Reperfusion Injury
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Xiao-Ping Yang, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail xpyang1{at}hfhs.org
Abstract—We tested the hypothesis that nitric oxide (NO) released by endothelial NO synthase (eNOS) is not only important in blood pressure regulation but also involved in cardiac function and remodeling and in the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEi). With the use of a 2D Doppler echocardiography system equipped with a 15-MHz linear transducer, we evaluated left ventricular (LV) morphology and function in conscious eNOS knockout mice (eNOS-/-; n=15) and their wild-type littermates (eNOS+/+; n=16). We also studied whether in eNOS-/- mice (1) myocardial ischemia/reperfusion injury is more severe and (2) the cardioprotective effect of ACEi is diminished or absent. In comparison with the wild type, eNOS-/- mice had significantly increased systolic blood pressure (128±3 versus 108±5 mm Hg; P<0.001) and decreased heart rate (531±22 versus 629±18 bpm; P<0.001) associated with increased LV posterior wall thickness (0.80±0.04 versus 0.64±0.02 mm; P<0.001) and LV mass (18.3±0.9 versus 13.1±0.5 mg/10 g body weight; P<0.01). Despite hypertension and LV hypertrophy, LV chamber dimension, shortening fraction and ejection fraction (indicators of LV contractility), and cardiac output did not differ between the 2 strains, which indicates that LV function in eNOS-/- mice is well compensated. We also found that in eNOS+/+ mice, ACEi decreased the ratio of myocardial infarct size to area at risk from 62.7±3.9% to 36.3±1.6% (P<0.001), whereas in eNOS-/- mice this effect of ACEi was almost abolished: the ratio of myocardial infarct size to area at risk was 67.2±2.9% in the vehicle-treated group and 62.7±3.9% in mice treated with ACEi. Moreover, infarct size in vehicle-treated eNOS-/- mice was not significantly different from eNOS+/+ mice given the same treatment. We concluded that (1) endothelium-derived NO plays an important role in the regulation of blood pressure homeostasis; (2) NO released under basal conditions has no significant impact on cardiac function; and (3) ACEi protect the heart against ischemia/reperfusion injury in mice and that this effect is mediated in part by endothelium-derived NO.
Key Words: nitric oxide • myocardial ischemia • myocardial reperfusion injury • mice, knockout • angiotensin-converting enzyme inhibitors • echocardiography
This article has been cited by other articles:
 |
|
 |
|
  J. L. Durand, S. Mukherjee, F. Commodari, A. P. De Souza, D. Zhao, F. S. Machado, H. B. Tanowitz, and L. A. Jelicks Role of NO Synthase in the Development of Trypanosoma cruzi-Induced Cardiomyopathy in Mice Am J Trop Med Hyg, May 1, 2009; 80(5): 782 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. A. Capettini, S. F. Cortes, M. A. Gomes, G. A. B. Silva, J. L. Pesquero, M. J. Lopes, M. M. Teixeira, and V. S. Lemos Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2503 - H2511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, M. J. Kohr, D. G. Wheeler, and M. T. Ziolo Endothelial nitric oxide synthase decreases {beta}-adrenergic responsiveness via inhibition of the L-type Ca2+ current Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1473 - H1480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Raher, H. Thibault, K. K. Poh, R. Liu, E. F. Halpern, G. Derumeaux, F. Ichinose, W. M. Zapol, K. D. Bloch, M. H. Picard, et al. In Vivo Characterization of Murine Myocardial Perfusion With Myocardial Contrast Echocardiography: Validation and Application in Nitric Oxide Synthase 3 Deficient Mice Circulation, September 11, 2007; 116(11): 1250 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, O. A. Carretero, C.-X. Lin, M. A. Cavasin, E. G. Shesely, J. J. Yang, T. L. Reudelhuber, and X.-P. Yang Role of cardiac overexpression of ANG II in the regulation of cardiac function and remodeling postmyocardial infarction Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1900 - H1907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Davidson and M. R. Duchen Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance Cardiovasc Res, July 1, 2006; 71(1): 10 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sun, O. A. Carretero, J. Xu, N.-E. Rhaleb, F. Wang, C. Lin, J. J. Yang, P. J. Pagano, and X.-P. Yang Lack of Inducible NO Synthase Reduces Oxidative Stress and Enhances Cardiac Response to Isoproterenol in Mice With Deoxycorticosterone Acetate-Salt Hypertension Hypertension, December 1, 2005; 46(6): 1355 - 1361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, O. A. Carretero, Y. Sun, E. G. Shesely, N.-E. Rhaleb, Y.-H. Liu, T.-D. Liao, J. J. Yang, M. Bader, and X.-P. Yang Role of the B1 Kinin Receptor in the Regulation of Cardiac Function and Remodeling After Myocardial Infarction Hypertension, April 1, 2005; 45(4): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Guthrie, L. M. Curtis, R. N. Mames, G. G. Simon, M. B. Grant, and E. W. Scott The nitric oxide pathway modulates hemangioblast activity of adult hematopoietic stem cells Blood, March 1, 2005; 105(5): 1916 - 1922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xiang, J. Kong, S. Chen, L.-P. Cao, G. Qiao, W. Zheng, W. Liu, X. Li, D. G. Gardner, and Y. C. Li Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E125 - E132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, N. Ahmad, M. Kudo, and M. Ashraf Contribution of Akt and endothelial nitric oxide synthase to diazoxide-induced late preconditioning Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1125 - H1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Momken, P. Lechene, R. Ventura-Clapier, and V. Veksler Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H914 - H920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Brede, W. Roell, O. Ritter, F. Wiesmann, R. Jahns, A. Haase, B. K. Fleischmann, and L. Hein Cardiac Hypertrophy Is Associated With Decreased eNOS Expression in Angiotensin AT2 Receptor-Deficient Mice Hypertension, December 1, 2003; 42(6): 1177 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fleming Brain in the Brawn: The Neuronal Nitric Oxide Synthase as a Regulator of Myogenic Tone Circ. Res., October 3, 2003; 93(7): 586 - 588. [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. Cappola, L. Cope, A. Cernetich, L. A. Barouch, K. Minhas, R. A. Irizarry, G. Parmigiani, S. Durrani, T. Lavoie, E. P. Hoffman, et al. Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy Physiol Genomics, June 24, 2003; 14(1): 25 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. N Van Vliet, L. L Chafe, and J.-P. Montani Characteristics of 24 h Telemetered Blood Pressure in eNOS-Knockout and C57Bl/6J Control Mice J. Physiol., May 15, 2003; 549(1): 313 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. McNamara, R. Holubkov, L. Postava, R. Ramani, K. Janosko, M. Mathier, G. A. MacGowan, S. Murali, A. M. Feldman, and B. London Effect of the Asp298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure Circulation, April 1, 2003; 107(12): 1598 - 1602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Ortiz and J. L. Garvin Cardiovascular and renal control in NOS-deficient mouse models Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R628 - R638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P B Massion and J-L Balligand Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice J. Physiol., January 1, 2003; 546(1): 63 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Brunner, R. Maier, P. Andrew, G. Wolkart, R. Zechner, and B. Mayer Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase Cardiovasc Res, January 1, 2003; 57(1): 55 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Endo, K. Kojima, K. Nakamura, Y. Matsuzaki, and T. Onitsuka Nitric oxide inhalation prompts weaning from the right ventricular assist device: Evaluation under continuous-flow biventricular assistance J. Thorac. Cardiovasc. Surg., October 1, 2002; 124(4): 739 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. A. Janssen and J. F. M. Smits Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1545 - R1564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Sharp, S. P. Jones, D. M. Rimmer, and D. J. Lefer Differential response to myocardial reperfusion injury in eNOS-deficient mice Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2422 - H2426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Y. H. Wong, S. Kulandavelu, K. J. Whiteley, D. Qu, B. L. Langille, and S. L. Adamson Maternal cardiovascular changes during pregnancy and postpartum in mice Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H918 - H925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, J. Xu, X.-P. Yang, F. Yang, E. Shesely, and O. A. Carretero Effect of ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists on Endothelial NO Synthase Knockout Mice With Heart Failure Hypertension, February 1, 2002; 39(2): 375 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Scherrer-Crosbie, R. Ullrich, K. D. Bloch, H. Nakajima, B. Nasseri, H. T. Aretz, M. L. Lindsey, A.-C. Vancon, P. L. Huang, R. T. Lee, et al. Endothelial Nitric Oxide Synthase Limits Left Ventricular Remodeling After Myocardial Infarction in Mice Circulation, September 11, 2001; 104(11): 1286 - 1291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fischer, A. A. MacLean, M. Liu, B. Kalirai, and S. Keshavjee Inhibition of angiotensin-converting enzyme by captopril: A novel approach to reduce ischemia-reperfusion injury after lung transplantation J. Thorac. Cardiovasc. Surg., September 1, 2000; 120(3): 573 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Hill, M. Karimi, W. Kutschke, R. L. Davisson, K. Zimmerman, Z. Wang, R. E. Kerber, and R. M. Weiss Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload Circulation, June 20, 2000; 101(24): 2863 - 2869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Yang, Y.-H. Liu, N.-E. Rhaleb, N. Kurihara, H. E. Kim, and O. A. Carretero Echocardiographic assessment of cardiac function in conscious and anesthetized mice Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1967 - H1974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Sharp, S. P. Jones, D. M. Rimmer, and D. J. Lefer Differential response to myocardial reperfusion injury in eNOS-deficient mice Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2422 - H2426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
|
|