This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Emanueli, C. Articles by Madeddu, P. Search for Related Content PubMed PubMed Citation Articles by Emanueli, C. Articles by Madeddu, P.

(Circulation. 1999;100:2359.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Dilated and Failing Cardiomyopathy in Bradykinin B₂ Receptor Knockout Mice

Costanza Emanueli, PhD¹; Roberta Maestri, PhD¹; Domenico Corradi, MD; Roberta Marchione, MD; Alessandra Minasi, PhD; Maria Grazia Tozzi, PhD; Maria Bonaria Salis, BS; Stefania Straino, BS; Maurizio C. Capogrossi, MD; Giorgio Olivetti, MD; Paolo Madeddu, MD

From the National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., P.M.), Osilo; Laboratorio di Patologia Vascolare (C.E., A.M., S.S., M.C.C.), Istituto Dermopatico dell’Immacolata, Rome; Department of Pathology (R.M., D.C., R.M., G.O.), University of Parma, Parma; and Institutes of Biochemistry (M.G.T.), Internal Medicine and Department of Biomedical Sciences (P.M.), University of Sassari, Sassari, Italy.

Correspondence to Paolo Madeddu, MD, Institute of Internal Medicine, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it

Background—The activation of B₂ receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure.

Methods and Results—To test whether the absence of bradykinin B₂ receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B₂ receptor gene knockout (B₂^-/-), heterozygous (B₂^+/-), and wild-type (B₂^+/+) mice. The BP of B₂^-/- mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B₂^+/+, P<0.01). In B₂^+/- mice, BP elevation was delayed. At 40 days, the heart rate was higher (P<0.01) in B₂^-/- and B₂^+/- than in B₂^+/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B₂^-/- and B₂^+/- mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B₂^+/+ mice. In B₂^-/- mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B₂^+/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B₂^+/+ mice, P<0.01), and reparative fibrosis.

Conclusions—The disruption of the bradykinin B₂ receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

Key Words: bradykinin • angiotensin • myocardium • hypertrophy • heart failure • blood pressure • genes

This article has been cited by other articles:

				M. A. Mori, R. C. Araujo, F. C.G. Reis, D. G. Sgai, R. G. Fonseca, C. C. Barros, V. F. Merino, M. Passadore, A. M. Barbosa, B. Ferrari, et al. Kinin B1 Receptor Deficiency Leads to Leptin Hypersensitivity and Resistance to Obesity Diabetes, June 1, 2008; 57(6): 1491 - 1500. [Abstract] [Full Text] [PDF]

				D. C. Isbell, S. Voros, Z. Yang, J. M. DiMaria, S. S. Berr, B. A. French, F. H. Epstein, S. P. Bishop, H. Wang, R. J. Roy, et al. Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3372 - H3378. [Abstract] [Full Text] [PDF]

				S. Helske, M. Laine, M. Kupari, J. Lommi, H. Turto, L. Nurmi, I. Tikkanen, K. Werkkala, K. A. Lindstedt, and P. T. Kovanen Increased expression of profibrotic neutral endopeptidase and bradykinin type 1 receptors in stenotic aortic valves Eur. Heart J., August 1, 2007; 28(15): 1894 - 1903. [Abstract] [Full Text] [PDF]

				C. Cayla, M. Todiras, R. Iliescu, V. V. Saul, V. Gross, B. Pilz, G. Chai, V. F. Merino, J. B. Pesquero, O. C. Baltatu, et al. Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension FASEB J, June 1, 2007; 21(8): 1689 - 1698. [Abstract] [Full Text] [PDF]

				I. Liesmaa, A. Kuoppala, N. Shiota, J. O. Kokkonen, K. Kostner, M. Mayranpaa, P. T. Kovanen, and K. A. Lindstedt Increased expression of bradykinin type-1 receptors in endothelium of intramyocardial coronary vessels in human failing hearts Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2317 - H2322. [Abstract] [Full Text] [PDF]

				J. Chao and L. Chao Kallikrein-kinin in stroke, cardiovascular and renal disease Exp Physiol, May 1, 2005; 90(3): 291 - 298. [Abstract] [Full Text] [PDF]

				L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]

				G. W. Booz Putting the Brakes on Cardiac Hypertrophy: Exploiting the NO-cGMP Counter-Regulatory System Hypertension, March 1, 2005; 45(3): 341 - 346. [Abstract] [Full Text] [PDF]

				T. Strecker, K. Messlinger, M. Weyand, and P. W. Reeh Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice Cardiovasc Res, February 1, 2005; 65(2): 405 - 410. [Abstract] [Full Text] [PDF]

				K. Funabiki, K. Onishi, K. Dohi, T. Koji, K. Imanaka-Yoshida, M. Ito, H. Wada, N. Isaka, T. Nobori, and T. Nakano Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2487 - H2492. [Abstract] [Full Text] [PDF]

				D. Tonduangu, L. Hittinger, B. Ghaleh, P. Le Corvoisier, L. Sambin, S. Champagne, T. Badoual, F. Vincent, A. Berdeaux, B. Crozatier, et al. Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs Circulation, January 6, 2004; 109(1): 114 - 119. [Abstract] [Full Text] [PDF]

				S. I. McFarlane, N. Winer, and J. R. Sowers Role of the Natriuretic Peptide System in Cardiorenal Protection Arch Intern Med, December 8, 2003; 163(22): 2696 - 2704. [Abstract] [Full Text] [PDF]

				G. Bledsoe, L. Chao, and J. Chao Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1479 - H1488. [Abstract] [Full Text] [PDF]

				C. Meune, J.-J. Mourad, J.-F. Bergmann, and C. Spaulding Interaction between cyclooxygenase and the renin-angiotensin-aldosterone system: rationale and clinical relevance Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 149 - 154. [Abstract] [PDF]

				A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]

				H. D. Xiao, S. Fuchs, J. M. Cole, K. M. Disher, R. L. Sutliff, and K. E. Bernstein Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting-Enzyme Systems: Role of bradykinin in angiotensin-converting enzyme knockout mice Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1969 - H1977. [Abstract] [Full Text] [PDF]

				R. Maestri, A. F. Milia, M. B. Salis, G. Graiani, C. Lagrasta, M. Monica, D. Corradi, C. Emanueli, and P. Madeddu Cardiac Hypertrophy and Microvascular Deficit in Kinin B2 Receptor Knockout Mice Hypertension, May 1, 2003; 41(5): 1151 - 1155. [Abstract] [Full Text] [PDF]

				D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]

				L. Murphey, D. Vaughan, and N. Brown Contribution of bradykinin to the cardioprotective effects of ACE inhibitors Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A37 - A41. [Abstract] [PDF]

				A. C. Rosenkranz, S. G. Hood, R. L. Woods, G. J. Dusting, and R. H. Ritchie Acute Antihypertrophic Actions of Bradykinin in the Rat Heart: Importance of Cyclic GMP Hypertension, October 1, 2002; 40(4): 498 - 503. [Abstract] [Full Text] [PDF]

				A. F. Milia, M. B. Salis, T. Stacca, A. Pinna, P. Madeddu, M. Trevisani, P. Geppetti, and C. Emanueli Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia Circ. Res., August 23, 2002; 91(4): 346 - 352. [Abstract] [Full Text] [PDF]

				C. Emanueli, M. B. Salis, A. Pinna, T. Stacca, A. F. Milia, A. Spano, J. Chao, L. Chao, L. Sciola, and P. Madeddu Prevention of Diabetes-Induced Microangiopathy by Human Tissue Kallikrein Gene Transfer Circulation, August 20, 2002; 106(8): 993 - 999. [Abstract] [Full Text] [PDF]

				A. Kuoppala, N. Shiota, J. O. Kokkonen, I. Liesmaa, K. Kostner, M. Mayranpaa, P. T. Kovanen, and K. A. Lindstedt Down-regulation of cardioprotective bradykinin type-2 receptors in the left ventricle of patients with end-stage heart failure J. Am. Coll. Cardiol., July 3, 2002; 40(1): 119 - 125. [Abstract] [Full Text] [PDF]

				F. Trabold, S. Pons, A. A. Hagege, M. Bloch-Faure, F. Alhenc-Gelas, J.-F. Giudicelli, C. Richer-Giudicelli, and P. Meneton Cardiovascular Phenotypes of Kinin B2 Receptor- and Tissue Kallikrein-Deficient Mice Hypertension, July 1, 2002; 40(1): 90 - 95. [Abstract] [Full Text] [PDF]

				C. Ozcelik, B. Erdmann, B. Pilz, N. Wettschureck, S. Britsch, N. Hubner, K. R. Chien, C. Birchmeier, and A. N. Garratt Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy PNAS, June 25, 2002; 99(13): 8880 - 8885. [Abstract] [Full Text] [PDF]

				M. Fujii, A. Wada, T. Tsutamoto, M. Ohnishi, T. Isono, and M. Kinoshita Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure Hypertension, May 1, 2002; 39(5): 952 - 957. [Abstract] [Full Text] [PDF]

				J. Stypmann, K. Glaser, W. Roth, D. J. Tobin, I. Petermann, R. Matthias, G. Monnig, W. Haverkamp, G. Breithardt, W. Schmahl, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L PNAS, April 18, 2002; (2002) 92637699. [Abstract] [Full Text] [PDF]

				J. Fielitz, A. Dendorfer, R. Pregla, E. Ehler, H. R. Zurbrugg, J. Bartunek, R. Hetzer, and V. Regitz-Zagrosek Neutral Endopeptidase Is Activated in Cardiomyocytes in Human Aortic Valve Stenosis and Heart Failure Circulation, January 22, 2002; 105(3): 286 - 289. [Abstract] [Full Text] [PDF]

				C. Emanueli, M. Bonaria Salis, T. Stacca, G. Pintus, R. Kirchmair, J. M. Isner, A. Pinna, L. Gaspa, D. Regoli, C. Cayla, et al. Targeting Kinin B1 Receptor for Therapeutic Neovascularization Circulation, January 22, 2002; 105(3): 360 - 366. [Abstract] [Full Text] [PDF]

				M. Majima, M. Katori, N.-E. Rhaleb, X.-P. Yang, M. Nanba, E. G. Shesely, O. A. Carretero, P. Madeddu, N.-E. Rhaleb, X.-P. Yang, et al. Effect of Chronic Blockade of the Kallikrein-Kinin System on the Development of Hypertension in Rats * Response * Role of Kinins in Blood Pressure Regulation: Reality or Fiction * Response Hypertension, October 1, 2001; 38 (4): e21 - e23. [Full Text] [PDF]

				K. T. Weber Cardioreparation in Hypertensive Heart Disease Hypertension, September 1, 2001; 38(3): 588 - 591. [Abstract] [Full Text] [PDF]

				J. L. Rouleau, G. Kapuku, S. Pelletier, H. Gosselin, A. Adam, C. Gagnon, C. Lambert, and S. Meloche Cardioprotective Effects of Ramipril and Losartan in Right Ventricular Pressure Overload in the Rabbit: Importance of Kinins and Influence on Angiotensin II Type 1 Receptor Signaling Pathway Circulation, August 21, 2001; 104(8): 939 - 944. [Abstract] [Full Text] [PDF]

				H. M. Siragy, M. de Gasparo, M. El-Kersh, and R. M. Carey Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP Hypertension, August 1, 2001; 38(2): 183 - 186. [Abstract] [Full Text] [PDF]

				C. G. Nebigil, P. Hickel, N. Messaddeq, J.-L. Vonesch, M. P. Douchet, L. Monassier, K. Gyorgy, R. Matz, R. Andriantsitohaina, P. Manivet, et al. Ablation of Serotonin 5-HT2B Receptors in Mice Leads to Abnormal Cardiac Structure and Function Circulation, June 19, 2001; 103(24): 2973 - 2979. [Abstract] [Full Text] [PDF]

				P. Meneton, M. Bloch-Faure, A. A. Hagege, H. Ruetten, W. Huang, S. Bergaya, D. Ceiler, D. Gehring, I. Martins, G. Salmon, et al. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice PNAS, February 15, 2001; (2001) 51619598. [Abstract] [Full Text]

				C. Emanueli, A. Minasi, A. Zacheo, J. Chao, L. Chao, M. B. Salis, S. Straino, M. G. Tozzi, R. Smith, L. Gaspa, et al. Local Delivery of Human Tissue Kallikrein Gene Accelerates Spontaneous Angiogenesis in Mouse Model of Hindlimb Ischemia Circulation, January 2, 2001; 103(1): 125 - 132. [Abstract] [Full Text] [PDF]

				C. Blais Jr., D. Fortin, J.-L. Rouleau, G. Molinaro, and A. Adam Protective Effect of Omapatrilat, a Vasopeptidase Inhibitor, on the Metabolism of Bradykinin in Normal and Failing Human Hearts J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 621 - 626. [Abstract] [Full Text]

				C. Emanueli, A. Zacheo, A. Minasi, J. Chao, L. Chao, M. B. Salis, T. Stacca, S. Straino, M. C. Capogrossi, and P. Madeddu Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Induces Angiogenesis in Normoperfused Skeletal Muscle Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2379 - 2385. [Abstract] [Full Text] [PDF]

				K. T. Weber Targeting Pathological Remodeling : Concepts of Cardioprotection and Reparation Circulation, September 19, 2000; 102(12): 1342 - 1345. [Full Text] [PDF]

				F. C. Luft STOPPING at the CAPPP of good HOPE Nephrol. Dial. Transplant., April 1, 2000; 15(4): 451 - 452. [Full Text] [PDF]

				M. Schachter ACE inhibitors, angiotensin receptor antagonists and bradykinin Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 27 - 29. [PDF]

				L. J. Dell’Italia and S. Oparil Bradykinin in the Heart : Friend Or Foe? Circulation, December 7, 1999; 100(23): 2305 - 2307. [Full Text] [PDF]

				P. Meneton, M. Bloch-Faure, A. A. Hagege, H. Ruetten, W. Huang, S. Bergaya, D. Ceiler, D. Gehring, I. Martins, G. Salmon, et al. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice PNAS, February 27, 2001; 98(5): 2634 - 2639. [Abstract] [Full Text] [PDF]

				J. Stypmann, K. Glaser, W. Roth, D. J. Tobin, I. Petermann, R. Matthias, G. Monnig, W. Haverkamp, G. Breithardt, W. Schmahl, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L PNAS, April 30, 2002; 99(9): 6234 - 6239. [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]

				S. C. FRANCIS, M. K. RAIZADA, A. A. MANGI, L. G. MELO, V. J. DZAU, P. R. VALE, J. M. ISNER, D. W. LOSORDO, J. CHAO, M. J. KATOVICH, et al. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics, December 21, 2001; 7(2): 79 - 94. [Abstract] [Full Text] [PDF]