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(Hypertension. 2001;37:1047.)
© 2001 American Heart Association, Inc.

Theodore Cooper Lecture

Tissue Angiotensin and Pathobiology of Vascular Disease

A Unifying Hypothesis

Victor J. Dzau

From the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Victor J. Dzau, MD, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, Tower 1 Room 210, Boston, MA 02115. E-mail vdzau{at}bics.bwh.harvard.edu

Abstract—There is increasing evidence that direct pathobiological events in the vessel wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactive oxygen species. Increased reactive oxygen species can inactivate NO and produce peroxynitrite. Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Taken together, angiotensin II can promote vasoconstriction, inflammation, thrombosis, and vascular remodeling. In this article, we propose a model that unifies the interrelationship among cardiovascular risk factors, angiotensin II, and the pathobiological mechanisms contributing to cardiovascular disease. This model may also explain the beneficial effects of ACE inhibitors on cardiovascular events beyond blood pressure reduction.

Key Words: cardiovascular diseases • endothelium-derived factor • molecular biology • risk factors • vasculature

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				E. Cerbai and A. Mugelli Angiotensin AT2 receptor: the younger sibling attracts attention Cardiovasc Res, April 1, 2004; 62(1): 7 - 8. [Full Text] [PDF]

				W. Ni, S. Kitamoto, M. Ishibashi, M. Usui, S. Inoue, K.-i. Hiasa, Q. Zhao, K.-i. Nishida, A. Takeshita, and K. Egashira Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 534 - 539. [Abstract] [Full Text]

				T. Jinno, M. Iwai, Z. Li, J.-M. Li, H.-W. Liu, T.-X. Cui, H. Rakugi, T. Ogihara, and M. Horiuchi Calcium Channel Blocker Azelnidipine Enhances Vascular Protective Effects of AT1 Receptor Blocker Olmesartan Hypertension, February 1, 2004; 43(2): 263 - 269. [Abstract] [Full Text] [PDF]

				A. Benetos, J. P. Gardner, M. Zureik, C. Labat, L. Xiaobin, C. Adamopoulos, M. Temmar, K. E. Bean, F. Thomas, and A. Aviv Short Telomeres Are Associated With Increased Carotid Atherosclerosis in Hypertensive Subjects Hypertension, February 1, 2004; 43(2): 182 - 185. [Abstract] [Full Text] [PDF]

				M. H. Alderman Dietary Sodium and Cardiovascular Health in Hypertensive Patients: The Case against Universal Sodium Restriction J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S47 - 50. [Abstract] [Full Text]

				J. Hwang, M. H. Ing, A. Salazar, B. Lassegue, K. Griendling, M. Navab, A. Sevanian, and T. K. Hsiai Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation Circ. Res., December 12, 2003; 93(12): 1225 - 1232. [Abstract] [Full Text] [PDF]

				S. Kinugawa, H. Post, P. M. Kaminski, X. Zhang, X. Xu, H. Huang, F. A. Recchia, M. Ochoa, M. S. Wolin, G. Kaley, et al. Coronary Microvascular Endothelial Stunning After Acute Pressure Overload in the Conscious Dog Is Caused by Oxidant Processes: The Role of Angiotensin II Type 1 Receptor and NAD(P)H Oxidase Circulation, December 9, 2003; 108(23): 2934 - 2940. [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]

				A. Moldobaeva and E. M. Wagner Angiotensin-converting enzyme activity in ovine bronchial vasculature J Appl Physiol, December 1, 2003; 95(6): 2278 - 2284. [Abstract] [Full Text]

				A. Stanton, C. Jensen, J. Nussberger, and E. O'Brien Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren Hypertension, December 1, 2003; 42(6): 1137 - 1143. [Abstract] [Full Text] [PDF]

				R. Chen, M. Iwai, L. Wu, J. Suzuki, L.-J. Min, T. Shiuchi, T. Sugaya, H.-W. Liu, T.-X. Cui, and M. Horiuchi Important Role of Nitric Oxide in the Effect of Angiotensin-Converting Enzyme Inhibitor Imidapril on Vascular Injury Hypertension, October 1, 2003; 42(4): 542 - 547. [Abstract] [Full Text] [PDF]

				S. Y. Chan, G. B. J. Mancini, L. Kuramoto, M. Schulzer, J. Frohlich, and A. Ignaszewski The prognostic importance of endothelial dysfunction and carotid atheromaburden in patients with coronary artery disease J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1037 - 1043. [Abstract] [Full Text] [PDF]

				H. D. Xiao, S. Fuchs, K. Frenzel, J. M. Cole, and K. E. Bernstein Newer Approaches to Genetic Modeling in Mice: Tissue-Specific Protein Expression as Studied Using Angiotensin-Converting Enzyme (ACE) Am. J. Pathol., September 1, 2003; 163(3): 807 - 817. [Full Text] [PDF]

				L. A. Calo, E. Pagnin, P. A. Davis, M. Sartori, and A. Semplicini Oxidative stress-related factors in Bartter's and Gitelman's syndromes: relevance for angiotensin II signalling Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1518 - 1525. [Abstract] [Full Text] [PDF]

				M. A Schmidt, A. K Chakrabarti, C. Kehrer, D. Pfeninnger, R. D Brook, N. Kaciroti, C. Duvernoy, A. A Killeen, and S. Rajagopalan Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298->Asp) variant in determining endothelial function in coronary artery disease Vascular Medicine, August 1, 2003; 8(3): 177 - 183. [Abstract] [PDF]

				L. A. Calo, E. Pagnin, P. A. Davis, M. Sartori, and A. Semplicini Oxidative stress-related factors in Bartter's and Gitelman's syndromes: relevance for angiotensin II signalling Nephrol. Dial. Transplant., August 1, 2003; 18(88): 1518 - 1525. [Abstract] [Full Text]

				S. P. Didion and F. M. Faraci Angiotensin II Produces Superoxide-Mediated Impairment of Endothelial Function in Cerebral Arterioles Stroke, August 1, 2003; 34(8): 2038 - 2042. [Abstract] [Full Text] [PDF]

				J. R. Privratsky, L. E. Wold, J. R. Sowers, M. T. Quinn, and J. Ren AT1 Blockade Prevents Glucose-Induced Cardiac Dysfunction in Ventricular Myocytes: Role of the AT1 Receptor and NADPH Oxidase Hypertension, August 1, 2003; 42(2): 206 - 212. [Abstract] [Full Text] [PDF]

				D. Georgiadis, F. Beau, B. Czarny, J. Cotton, A. Yiotakis, and V. Dive Roles of the Two Active Sites of Somatic Angiotensin-Converting Enzyme in the Cleavage of Angiotensin I and Bradykinin: Insights From Selective Inhibitors Circ. Res., July 25, 2003; 93(2): 148 - 154. [Abstract] [Full Text] [PDF]

				G. Desideri, M. C. Bravi, M. Tucci, G. Croce, M. C. Marinucci, A. Santucci, E. Alesse, and C. Ferri Angiotensin II Inhibits Endothelial Cell Motility Through an AT1-Dependent Oxidant-Sensitive Decrement of Nitric Oxide Availability Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1218 - 1223. [Abstract] [Full Text] [PDF]

				J. Shao, M. Nangaku, T. Miyata, R. Inagi, K. Yamada, K. Kurokawa, and T. Fujita Imbalance of T-Cell Subsets in Angiotensin II-Infused Hypertensive Rats With Kidney Injury Hypertension, July 1, 2003; 42(1): 31 - 38. [Abstract] [Full Text] [PDF]

				J. M. Cole, H. Xiao, J. W. Adams, K. M. Disher, H. Zhao, and K. E. Bernstein New approaches to genetic manipulation of mice: tissue-specific expression of ACE Am J Physiol Renal Physiol, April 1, 2003; 284(4): F599 - F607. [Abstract] [Full Text] [PDF]

				A. Stanton Review: Potential of renin inhibition in cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 6 - 10. [Abstract] [PDF]

				M Hamon, S Fradin, A Denizet, E Filippi-Codaccioni, G Grollier, and R Morello Prospective evaluation of the effect of an angiotensin I converting enzyme gene polymorphism on the long term risk of major adverse cardiac events after percutaneous coronary intervention Heart, March 1, 2003; 89(3): 321 - 325. [Abstract] [Full Text] [PDF]

				P. Manohar and I. L. Pina Therapeutic Role of Angiotensin II Receptor Blockers in the Treatment of Heart Failure Mayo Clin. Proc., March 1, 2003; 78(3): 334 - 338. [Abstract] [PDF]

				D. J. Campbell Vasopeptidase Inhibition: A Double-Edged Sword? Hypertension, March 1, 2003; 41(3): 383 - 389. [Abstract] [Full Text] [PDF]