(Hypertension. 1997;30:128-133.)
© 1997 American Heart Association, Inc.
Articles |
Blood Pressures and Cardiovascular Homeostasis in Mice Having Reduced or Absent Angiotensin-Converting Enzyme Gene Function
From the Vascular Biology and Hypertension Program of the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham (B.T., Q.C.M., Y.-F.C., S.O.), and Departments of Internal Medicine (J.H.K.) and Pathology (J.H.K., O.S.), University of North Carolina at Chapel Hill.
Correspondence to Suzanne Oparil, MD, 1034 Zeigler Building, 703 S 19th St, University of Alabama at Birmingham, Birmingham, AL, 35294-0007. E-mail card027{at}uabdpo.dpo.uab.edu
Abstract We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/-), and homozygous mutant (-/-) mice for an insertional inactivation of the angiotensin-converting enzyme (ACE) gene (Ace in mice, ACE in humans). Compared with +/+ mice, baseline mean arterial pressure was not significantly altered in +/- mice but was reduced by 51±4 mm Hg in -/- mice. Although the pressor response to injected angiotensin II did not differ significantly in the three genotypic groups, the pressor response to angiotensin I was strongly affected by Ace genotype: Compared with the response in the +/+ group (+26% of baseline), the response to Ang I was close to half normal (+12%) in the +/- group and virtually abolished (+1%) in the -/- group. The depressor response to injected bradykinin was significantly enhanced in the +/- and -/- groups compared with the +/+ group. Ace expression and ACE activity were directly related to functional Ace copy number, and renin and angiotensinogen mRNA levels were inversely related to Ace copy number. Angiotensin type 1A receptor mRNA levels were not significantly different in the +/+, +/-, and -/- groups. We conclude that (1) ACE is essential for the maintenance of normal blood pressure; (2) subnormal levels of ACE affect the blood pressure responses to infused angiotensin I and bradykinin in vivo; and (3) compensations for inactivation of one Ace copy, which include increased expression of renin, normalize blood pressure in heterozygotes.
Key Words: gene targeting • renin • angiotensin I • angiotensin II • bradykinin
This article has been cited by other articles:
 |
|
 |
|
  E. Q. Haxhija, H. Yang, A. U. Spencer, H. Koga, X. Sun, and D. H. Teitelbaum Modulation of mouse intestinal epithelial cell turnover in the absence of angiotensin converting enzyme Am J Physiol Gastrointest Liver Physiol, July 1, 2008; 295(1): G88 - G98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Mullins, M. A. Bailey, and J. J. Mullins Hypertension, Kidney, and Transgenics: A Fresh Perspective Physiol Rev, April 1, 2006; 86(2): 709 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yoneda, H. Sanada, J. Yatabe, S. Midorikawa, S. Hashimoto, M. Sasaki, T. Katoh, T. Watanabe, P. M. Andrews, P. A. Jose, et al. Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats Hypertension, July 1, 2005; 46(1): 58 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Heimann, M. H. Favarato, F. C. Gozzo, V. Rioli, F. R. Carreno, M. N. Eberlin, E. S. Ferro, J. H. Krege, and J. E. Krieger ACE gene titration in mice uncovers a new mechanism for ACE on the control of body weight Physiol Genomics, January 20, 2005; 20(2): 173 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Santhamma, R. Sadhukhan, M. Kinter, S. Chattopadhyay, B. McCue, and I. Sen Role of Tyrosine Phosphorylation in the Regulation of Cleavage Secretion of Angiotensin-converting Enzyme J. Biol. Chem., September 17, 2004; 279(38): 40227 - 40236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Kessler, P. deS. Senanayake, T. S. Scheidemantel, J. B. Gomos, T. M. Rowe, and G. C. Sen Maintenance of Normal Blood Pressure and Renal Functions Are Independent Effects of Angiotensin-converting Enzyme J. Biol. Chem., May 30, 2003; 278(23): 21105 - 21112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Scholzen, S. Stander, H. Riemann, T. Brzoska, and T. A. Luger Modulation of Cutaneous Inflammation by Angiotensin-Converting Enzyme J. Immunol., April 1, 2003; 170(7): 3866 - 3873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Cole, N. Khokhlova, R. L. Sutliff, J. W. Adams, K. M. Disher, H. Zhao, M. R. Capecchi, P. Corvol, and K. E. Bernstein Mice Lacking Endothelial ACE: Normal Blood Pressure With Elevated Angiotensin II Hypertension, February 1, 2003; 41(2): 313 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Wei, B. Tian, G. Perry, Q. C. Meng, Y.-F. Chen, S. Oparil, and L. J. Dell'Italia Differential ANG II generation in plasma and tissue of mice with decreased expression of the ACE gene Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2254 - H2258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Kessler, J. B. Gomos, T. S. Scheidemantel, T. M. Rowe, H. L. Smith, and G. C. Sen The Germinal Isozyme of Angiotensin-converting Enzyme Can Substitute for the Somatic Isozyme in Maintaining Normal Renal Structure and Functions J. Biol. Chem., February 1, 2002; 277(6): 4271 - 4276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Carlson, S. Oparil, Y.-F. Chen, and J. M. Wyss Blood Pressure and NaCl-Sensitive Hypertension Are Influenced by Angiotensin-Converting Enzyme Gene Expression in Transgenic Mice Hypertension, February 1, 2002; 39(2): 214 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.B. GURLEY, T.H. LE, and T.M. COFFMAN Gene-targeting Studies of the Renin-Angiotensin System: Mechanisms of Hypertension and Cardiovascular Disease Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 451 - 458. [Abstract] [PDF]
|
|
|
|
 |
|
 B. C. Cholewa and D. L. Mattson Role of the renin-angiotensin system during alterations of sodium intake in conscious mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R987 - R993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Perry, T. Mori, C.-C. Wei, X. Y. Xu, Y.-F. Chen, S. Oparil, P. Lucchesi, and L. J. Dell'Italia Genetic Variation in Angiotensin-Converting Enzyme Does Not Prevent Development of Cardiac Hypertrophy or Upregulation of Angiotensin II in Response to Aortocaval Fistula Circulation, February 20, 2001; 103(7): 1012 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. E. S. Sibinga and J. A. Ware A Pair of ACEs, for Openers? Circ. Res., September 29, 2000; 87(7): 523 - 525. [Full Text] [PDF]
|
|
|
|
|
|
T. Rankinen, J. Gagnon, L. Perusse, Y. C. Chagnon, T. Rice, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H368 - H374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Rankinen, L. Perusse, J. Gagnon, Y. C. Chagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard Angiotensin-converting enzyme ID polymorphism and fitness phenotype in the HERITAGE Family Study J Appl Physiol, March 1, 2000; 88(3): 1029 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. CERVENKA, K. D. MITCHELL, and L. G. NAVAR Renal Function in Mice: Effects of Volume Expansion and AngiotensinII J. Am. Soc. Nephrol., December 1, 1999; 10(12): 2631 - 2636. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Traynor, T. Yang, Y. G. Huang, J. H. Krege, J. P. Briggs, O. Smithies, and J. Schnermann Tubuloglomerular feedback in ACE-deficient mice Am J Physiol Renal Physiol, May 1, 1999; 276(5): F751 - F757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson and K. R. Krauski Chronic Sodium Balance and Blood Pressure Response to Captopril in Conscious Mice Hypertension, November 1, 1998; 32(5): 923 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A Doevendans, M. J. Daemen, E. D de Muinck, and J. F Smits Cardiovascular phenotyping in mice Cardiovasc Res, July 1, 1998; 39(1): 34 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Kessler, T. M. Rowe, J. B. Gomos, P. M. Kessler, and G. C. Sen Physiological Non-equivalence of the Two Isoforms of Angiotensin-converting Enzyme J. Biol. Chem., August 18, 2000; 275(34): 26259 - 26264. [Abstract] [Full Text] [PDF]
|
|