Published Online
on July 21, 2003

A more recent version of this article appeared on August 5, 2003

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Submitted on December 12, 2002
Revised on April 15, 2003
Accepted on April 18, 2003

Activation and Functional Significance of the Renin-Angiotensin System in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor

Markus Flesch MD, Anje Höper MD, Louis Dell'Italia MD, Kenda Evans PhD, Richard Bond PhD, Ronald Peshock MD, Abhinav Diwan MBBS, Theresa A. Brinsa BS, Chih-Chang Wei PhD, Natarajan Sivasubramanian PhD, Francis G. Spinale MD, PhD, and Douglas L. Mann MD^*

From the Winters Center for Heart Failure Research, Cardiology Section of Department of Medicine, Houston VAMC and Baylor College of Medicine, Houston, Tex (M.F., A.H., A.D., N.S., D.L.M.); Department of Medicine, University of Alabama, Birmingham (L.D.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Tex (K.E., R.B.); Department of Radiology, Texas Southwestern University, Dallas, Tex (R.P., C.-C.W.); and Department of Surgery, Cardiothoracic Research, Medical University of South Carolina, Charleston (T.A.B., F.G.S.).

^* To whom correspondence should be addressed. E-mail: dmann{at}bcm.tmc.edu.

Background--The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart.

Methods and Results--We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis.

Conclusions--Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling.

Key words: hypertrophy • genes • heart failure • remodeling • apoptosis

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