Advertisement

Vascular wall ACE is not required for atherogenesis in ApoE−/− mice

  • Daiana Weiss
    Affiliations
    Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
    Search for articles by this author
  • Kenneth E. Bernstein
    Affiliations
    Department of Pathology, Emory University School of Medicine, Atlanta, GA, United States

    Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States

    Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
    Search for articles by this author
  • Sebastian Fuchs
    Affiliations
    Department of Pathology, Emory University School of Medicine, Atlanta, GA, United States

    Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States

    Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
    Search for articles by this author
  • Jonathan Adams
    Affiliations
    Department of Pathology, Emory University School of Medicine, Atlanta, GA, United States
    Search for articles by this author
  • Andreas Synetos
    Affiliations
    Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
    Search for articles by this author
  • W. Robert Taylor
    Correspondence
    Corresponding author at: Cardiology Division, Emory University School of Medicine, 1639 Pierce Drive, Suite 319 WMB, Atlanta, GA 30322, United States. Tel.: +1 404 727 8921; fax: +1 404 727 3572.
    Affiliations
    Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States

    The Atlanta VA Medical Center, Decatur, GA, United States

    The Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine, Atlanta, GA, United States
    Search for articles by this author

      Abstract

      Background

      It has been proposed that elements of the renin angiotensin system expressed in the arterial wall are critical for the development of atherosclerosis. Angiotensin converting enzyme (ACE) is highly expressed by the endothelium and is responsible for a critical enzymatic step in the generation of angiotensin II. However, the functional contribution of ACE expression in the vascular wall in atherogenesis is unknown. Therefore, we made use of unique genetic models in which mice without the expression of ACE in the vascular wall were crossed with ApoE−/− mice in order to determine the contribution of tissue ACE expression to atherosclerotic lesion formation.

      Methods and results

      Mice expressing either a soluble form of ACE (ACE 2/2) or mice with somatic ACE expression restricted to the liver and kidney (ACE 3/3) on an ApoE−/− background were placed on a standard chow or Western diet for 6 months. Atherosclerotic lesion area in the ACE 2/2 mice was significantly lower than that seen in the ACE 3/3 mice. However, these animals also had significantly lower blood pressure and reduced plasma ACE activity which precluded establishing a specific causal relationship between absent tissue ACE activity and decreased atherosclerotic lesion extent. Therefore, we studied the ACE 3/3 mice which are normotensive and lack vascular ACE expression. In the ACE 3/3 animals, atherosclerotic lesion area was not different from wild type controls despite reduced plasma ACE activity.

      Conclusions

      We concluded that under these experimental conditions, expression of ACE in the arterial wall is not required for atherosclerotic lesion formation.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Daugherty A.
        • Cassis L.
        Angiotensin II-mediated development of vascular diseases.
        Trends Cardiovasc Med. 2004; 14: 117-120
        • Dzau V.J.
        Theodore Cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis.
        Hypertension. 2001; 37: 1047-1052
        • Gibbons G.H.
        The pathophysiology of hypertension: the importance of angiotensin II in cardiovascular remodeling.
        Am J Hypertens. 1998; 11: 177S-181S
        • Griendling K.K.
        • Ushio-Fukai M.
        Reactive oxygen species as mediators of angiotensin II signaling.
        Regul Pept. 2000; 91: 21-27
        • Griendling K.K.
        • Ushio-Fukai M.
        • Lassegue B.
        • Alexander R.W.
        Angiotensin II signaling in vascular smooth muscle. New concepts.
        Hypertension. 1997; 29: 366-373
        • Weiss D.
        • Sorescu D.
        • Taylor W.R.
        Angiotensin II and atherosclerosis.
        Am J Cardiol. 2001; 87: 25C-32C
        • Dzau V.J.
        • Bernstein K.
        • Celermajer D.
        • Cohen J.
        • Dahlof B.
        • Deanfield J.
        • et al.
        The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data.
        Am J Cardiol. 2001; 88: 1L-20L
        • Lee M.A.
        • Bohm M.
        • Paul M.
        • Ganten D.
        Tissue renin-angiotensin systems. Their role in cardiovascular disease.
        Circulation. 1993; 87: IV7-13
        • Potter D.D.
        • Sobey C.G.
        • Tompkins P.K.
        • Rossen J.D.
        • Heistad D.D.
        Evidence that macrophages in atherosclerotic lesions contain angiotensin II.
        Circulation. 1998; 98: 800-807
        • Okamura A.
        • Rakugi H.
        • Ohishi M.
        • Yanagitani Y.
        • Takiuchi S.
        • Moriguchi K.
        • et al.
        Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages.
        J Hypertens. 1999; 17: 537-545
        • Diet F.
        • Pratt R.E.
        • Berry G.J.
        • Momose N.
        • Gibbons G.H.
        • Dzau V.J.
        Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease.
        Circulation. 1996; 94: 2756-2767
        • Dzau V.J.
        • Bernstein K.
        • Celermajer D.
        • Cohen J.
        • Dahlof B.
        • Deanfield J.
        • et al.
        Pathophysiologic and therapeutic importance of tissue ACE: a consensus report.
        Cardiovasc Drugs Ther. 2002; 16: 149-160
        • Schiffrin E.L.
        Beyond blood pressure: the endothelium and atherosclerosis progression.
        Am J Hypertens. 2002; 15: 115S-122S
        • Esther C.R.
        • Marino E.M.
        • Howard T.E.
        • Machaud A.
        • Corvol P.
        • Capecchi M.R.
        • et al.
        The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.
        J Clin Invest. 1997; 99: 2375-2385
        • Shen X.Z.
        • Xiao H.D.
        • Li P.
        • Lin C.X.
        • Billet S.
        • Okwan-Duodu D.
        • et al.
        New insights into the role of angiotensin-converting enzyme obtained from the analysis of genetically modified mice.
        J Mol Med. 2008; 86: 679-684
        • Cole J.
        • Quach D.L.
        • Sundaram K.
        • Corvol P.
        • Capecchi M.R.
        • Bernstein K.E.
        Mice lacking endothelial angiotensin-converting enzyme have a normal blood pressure.
        Circ Res. 2002; 90: 87-92
        • Esther Jr., C.R.
        • Howard T.E.
        • Marino E.M.
        • Goddard J.M.
        • Capecchi M.R.
        • Bernstein K.E.
        Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility.
        Lab Invest. 1996; 74: 953-965
        • Weiss D.
        • Kools J.J.
        • Taylor W.R.
        Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice.
        Circulation. 2001; 103: 448-454
        • Cole J.M.
        • Khokhlova N.
        • Sutliff R.L.
        • Adams J.W.
        • Disher K.M.
        • Zhao H.
        • et al.
        Mice lacking endothelial ACE: normal blood pressure with elevated angiotensin II.
        Hypertension. 2003; 41: 313-321
        • Kon V.
        • Jabs K.
        Angiotensin in atherosclerosis.
        Curr Opin Nephrol Hypertens. 2004; 13: 291-297
        • Ferrario C.M.
        • Richmond R.S.
        • Smith R.
        • Levy P.
        • Strawn W.B.
        • Kivlighn S.
        Renin-angiotensin system as a therapeutic target in managing atherosclerosis.
        Am J Ther. 2004; 11: 44-53
        • Kowala M.C.
        • Grove R.I.
        • Aberg G.
        Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophage-foam cell accumulation independently of blood pressure and plasma lipids.
        Atherosclerosis. 1994; 108: 61-72
        • Hope S.
        • Brecher P.
        • Chobanian A.V.
        Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis.
        Am J Hypertens. 1999; 12: 28-34
        • Hayek T.
        • Attias J.
        • Coleman R.
        • Brodsky S.
        • Smith J.
        • Breslow J.L.
        • et al.
        The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice.
        Cardiovasc Res. 1999; 44: 579-587
        • Sun Y.P.
        • Zhu B.Q.
        • Browne A.E.
        • Pulukurthy S.
        • Chou T.M.
        • Sudhir K.
        • et al.
        Comparative effects of ACE inhibitors and an angiotensin receptor blocker on atherosclerosis and vascular function.
        J Cardiovasc Pharmacol Ther. 2001; 6: 175-181
        • Candido R.
        • Jandeleit-Dahm K.A.
        • Cao Z.
        • Nesteroff S.P.
        • Burns W.C.
        • Twigg S.M.
        • et al.
        Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice.
        Circulation. 2002; 106: 246-253
        • Schuh J.R.
        • Blehm D.J.
        • Frierdich G.E.
        • McMahon E.G.
        • Blaine E.H.
        Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.
        J Clin Invest. 1993; 91: 1453-1458
        • Keidar S.
        • Attias J.
        • Coleman R.
        • Wirth K.
        • Scholkens B.
        • Hayek T.
        Attenuation of atherosclerosis in apolipoprotein E-deficient mice by ramipril is dissociated from its antihypertensive effect and from potentiation of bradykinin.
        J Cardiovasc Pharmacol. 2000; 35: 64-72
        • Hayek T.
        • Attias J.
        • Smith J.
        • Breslow J.L.
        • Keidar S.
        Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice.
        J Cardiovasc Pharmacol. 1998; 31: 540-544
        • da Cunha V.
        • Tham D.M.
        • Martin-McNulty B.
        • Deng G.
        • Ho J.J.
        • Wilson D.W.
        • et al.
        Enalapril attenuates angiotensin II-induced atherosclerosis and vascular inflammation.
        Atherosclerosis. 2005; 178: 9-17
        • Wassmann S.
        • Czech T.
        • van Eickels M.
        • Fleming I.
        • Bohm M.
        • Nickenig G.
        Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice.
        Circulation. 2004; 110: 3062-3067
        • Daugherty A.
        • Manning M.W.
        • Cassis L.A.
        Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.
        J Clin Invest. 2000; 105: 1605-1612
        • Daugherty A.
        • Cassis L.
        Chronic angiotensin II infusion promotes atherogenesis in low density lipoprotein receptor −/− mice.
        Ann N Y Acad Sci. 1999; 892: 108-118
        • Hayek T.
        • Pavlotzky E.
        • Hamoud S.
        • Coleman R.
        • Keidar S.
        • Aviram M.
        • et al.
        Tissue angiotensin-converting-enzyme (ACE) deficiency leads to a reduction in oxidative stress and in atherosclerosis: studies in ACE-knockout mice type 2.
        Arteriosc Thromb Vasc Biol. 2003; 23: 2090-2096
        • Weiss D.
        • Taylor W.R.
        Deoxycorticosterone acetate salt hypertension in apolipoprotein E−/− mice results in accelerated atherosclerosis: the role of angiotensin II.
        Hypertension. 2008; 51: 218-224
        • Petrov V.
        • Fagard R.
        • Lijnen P.
        Effect of protease inhibitors on angiotensin-converting enzyme activity in human T-lymphocytes.
        Am J Hypertens. 2000; 13: 535-539
      1. Lu H, Rateri DL, Feldman DL, Jr RJ, Fukamizu A, Ishida J, Oesterling EG, Cassis LA, Daugherty A. Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J Clin Invest 2008;118(3):984–93.