The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data - 03/09/11

Doi : 10.1016/S0002-9149(01)01878-1

Victor J. Dzau, MD ⁎, ^a, Kenneth Bernstein, MD ^b, David Celermajer, MBBS, PhD ^c, Jerome Cohen, MD ^a,^d, Björn Dahlöf, MD, PhD ^e, John Deanfield, MD ^f, Javier Diez, MD, PhD ^g, Helmut Drexler, MD ^h, Roberto Ferrari, MD ⁱ, Wiek van Gilst, PhD ^j, Lennart Hansson, MD ^k, Burkhard Hornig, MD ^h, Ahsan Husain, PhD ^l, Colin Johnston, MD ^m, Harold Lazar, MD ⁿ, Eva Lonn, MD ^o, Thomas Lüscher, MD ^p, John Mancini, MD ^q, Albert Mimran, MD ^r, Carl Pepine, MD ^s, Ton Rabelink, MD, PhD ^t, Willem Remme, MD, PhD ^u, Luis Ruilope, MD ^v, Marcel Ruzicka, MD ^w, Heribert Schunkert, MD ^x, Karl Swedberg, MD ^y, Thomas Unger, MD ^z, Douglas Vaughan, MD ^aa, Michael Weber, MD ^bb
^a Brigham Women’s Hospital, Department of Medicine, Boston, Massachusetts, USA (VJD)
^b Emory University School of Medicine, Department of Pathology and Laboratory Medicine, Atlanta, Georgia, USA (KB)
^c University of Sydney, Department of Medicine, c/o Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (DC)
^d Saint Louis University School of Medicine, Department of Internal Medicine, Saint Louis, Missouri, USA (JC)
^e Sahlgrenska University Hospital/Ostra, Department of Medicine, Nilssonsberg, Sweden (BD)
^f Great Ormond Street Hospital for Children, Vascular Physiology Unit, London, United Kingdom (J Deanfield)
^g Universidad de Navarra, Unidad de Fisiopatologia Vascular, Edificio de Ciencias, Calle Iruniarrea, Pampalona, Spain (J Diez)
^h Medizinische Hochschule Hannover, Department of Cardiology, Hannover, Germany (HD, BH)
ⁱ Nuove Cliniche, Department of Clinical and Experimental Medicine, Corso Ferrara, Italy (RF)
^j University Hospital Groningen, Department of Clinical Pharmacology, Groningen, the Netherlands (WVG)
^k University of Uppsala, Clinical Hypertension Research, Uppsala, Sweden (LH)
^l Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia (AH)
^m Baker Institute, Melbourne, Australia (CJ)
ⁿ Boston Medical Center, Department of Cardiothoracic Surgery, Boston, Massachusetts, USA (HL)
^o Hamilton General Hospital-McMaster Clinic, Division of Cardiology, Hamilton, Ontario, Canada (EL)
^p University Hospital Zurich, Division of Cardiology, Zurich, Switzerland (TL)
^q Vancouver General Hospital, Department of Medicine, Vancouver, British Columbia, Canada (JM)
^r Hospital Lapeyronie, Medecine Interne et Hypertension Arterielle, Centre Hospitalier, Universitaire, Montpellier, France (AM)
^s University of Florida Gainesville, Division of Cardiovascular Medicine, Gainesville, Florida, USA (CP)
^t University Hospital Utrecht, Department of Internal Medicine, Utrecht, the Netherlands (TR)
^u Sticares Cardiovascular Research Foundation, Rhoon, the Netherlands (WR)
^v Unidad de Hypertension, Hospital, Madrid, Spain (LR)
^w University of Ottawa Heart Institute, Ottawa, Ontario, Canada (MR)
^x Klinik und Poliklinik fur Innere Medizin II, Franz-Josef-Strauss-Allee, Regensburg, Germany (HS)
^y Sahlgrenska University Hospital/Ostra, Göteberg, Sweden (KS)
^z Christian-Albrechts-University Kiel, Kiel, Germany (TU)
^aa Vanderbilt University School of Medicine, Division of Nashville, Tennessee, USA (DV)
^bb Brookdale Hospital, Department of Medicine, Brooklyn, New York, USA (MW)

Address for reprints: Victor J. Dzau, MD, Brigham Women’s Hospital, 75 Francis Street, Suite 210, Tower 1, Boston, Massachusetts 02115, USA

Abstract

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.

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