title: Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor.
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.
  
  
  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.affiliation: Winters Center for Heart Failure Research, Cardiology Section of Department of Medicine, Houston VAMC and Baylor College of Medicine, Houston, Tex 77030, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Flesch
authors.forename: Anje
authors.initials: A
authors.lastname: Höper
authors.forename: Louis
authors.initials: L
authors.lastname: Dell'Italia
authors.forename: Kenda
authors.initials: K
authors.lastname: Evans
authors.forename: Richard
authors.initials: R
authors.lastname: Bond
authors.forename: Ronald
authors.initials: R
authors.lastname: Peshock
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Brinsa
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Wei
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000367:Age Factors; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D009928:Organ Specificity; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; D000808:Angiotensinogen; D000804:Angiotensin II; D003094:Collagen; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D019808:Losartan