Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice.
OBJECTIVE
This study examined the role of angiotensin II (Ang-II) in a murine model of viral myocarditis.


BACKGROUND
Ang-II plays an important role in the pathophysiology of various cardiovascular disorders. However, the role of Ang-II in inflammatory heart diseases is not known.


METHODS
Four-week-old wild-type (WT) and Ang-II type 1 receptor (AT(1)R) knockout (KO) mice were inoculated with the encephalomyocarditis virus (EMCV). Survival, histopathology, expression of proinflammatory cytokines, and activity of nuclear factor-kappa B (NF-kB) in the heart were examined.


RESULTS
The 14-day survival was significantly increased in KO compared with WT mice. Histopathologic scores for myocardial necrosis (0.86 +/- 0.69 vs. 2.44 +/- 0.88, p < 0.01) and cellular infiltration (0.86 +/- 0.38 vs. 2.33 +/- 0.50, p < 0.01) were lower in KO than in WT mice. The expression of tumor necrosis factor-alpha (TNF-alpha) was increased 43.2-fold, that of interleukin-1-beta (IL-1-beta) 45.8-fold, and the activity of NF-kB 2.24-fold by EMCV inoculation in WT mice (each p < 0.01), but not in KO mice (5.9-fold, 6.3-fold, and 1.12-fold, respectively, each p = NS). The AT(1)R blocker also significantly attenuated the expression of proinflammatory cytokines and the activation of NF-kB in virus-inoculated WT mice. Intravenous Ang-II injection enhanced the activation of NF-kB (2.28-fold, p < 0.01) and increased the expression of TNF-alpha (2.31-fold, p < 0.01) and IL-1-beta (2.45-fold, p < 0.01) in heart tissue of WT but not KO mice.


CONCLUSIONS
These results indicate that the AT(1)R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II via the NF-kB/cytokine pathway.
Yamamoto
Kanjo
K
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shioi
Tetsuo
T
Uchiyama
Koji
K
Miyamoto
Tadashi
T
Sasayama
Shigetake
S
Matsumori
Akira
A
D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D018188:Cardiovirus Infections / Q000209:etiology* / Q000473:pathology; D004686:Encephalomyocarditis virus / Q000302:isolation & purification; D006321:Heart / Q000821:virology; D007375:Interleukin-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000209:etiology* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C077793:candesartan cilexetil