Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor.
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.
Flesch
Markus
M
Winters Center for Heart Failure Research, Cardiology Section of Department of Medicine, Houston VAMC and Baylor College of Medicine, Houston, Tex 77030, USA.
Höper
Anje
A
Dell'Italia
Louis
L
Evans
Kenda
K
Bond
Richard
R
Peshock
Ronald
R
Diwan
Abhinav
A
Brinsa
Theresa A
TA
Wei
Chih-Chang
CC
Sivasubramanian
Natarajan
N
Spinale
Francis G
FG
Mann
Douglas L
DL
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
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