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Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor.
Circulation. 2003 Aug 05; 108(5):598-604.Circ

Abstract

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.

Authors+Show Affiliations

Winters Center for Heart Failure Research, Cardiology Section of Department of Medicine, Houston VAMC and Baylor College of Medicine, Houston, Tex 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12874189

Citation

Flesch, Markus, et al. "Activation and Functional Significance of the Renin-angiotensin System in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor." Circulation, vol. 108, no. 5, 2003, pp. 598-604.
Flesch M, Höper A, Dell'Italia L, et al. Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. 2003;108(5):598-604.
Flesch, M., Höper, A., Dell'Italia, L., Evans, K., Bond, R., Peshock, R., Diwan, A., Brinsa, T. A., Wei, C. C., Sivasubramanian, N., Spinale, F. G., & Mann, D. L. (2003). Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. Circulation, 108(5), 598-604.
Flesch M, et al. Activation and Functional Significance of the Renin-angiotensin System in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor. Circulation. 2003 Aug 5;108(5):598-604. PubMed PMID: 12874189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. AU - Flesch,Markus, AU - Höper,Anje, AU - Dell'Italia,Louis, AU - Evans,Kenda, AU - Bond,Richard, AU - Peshock,Ronald, AU - Diwan,Abhinav, AU - Brinsa,Theresa A, AU - Wei,Chih-Chang, AU - Sivasubramanian,Natarajan, AU - Spinale,Francis G, AU - Mann,Douglas L, Y1 - 2003/07/21/ PY - 2003/7/23/pubmed PY - 2003/9/16/medline PY - 2003/7/23/entrez SP - 598 EP - 604 JF - Circulation JO - Circulation VL - 108 IS - 5 N2 - 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/12874189/Activation_and_functional_significance_of_the_renin_angiotensin_system_in_mice_with_cardiac_restricted_overexpression_of_tumor_necrosis_factor_ L2 - https://www.ahajournals.org/doi/10.1161/01.CIR.0000081768.13378.BF?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -