Shoken Honsho1, Susumu Nishikawa1, Katsuya Amano1, Kan Zen1, Yasushi Adachi1, Eigo Kishita1, Akihiro Matsui1, Asako Katsume1, Shinichiro Yamaguchi1, Kenichiro Nishikawa1, Kikuo Isoda1, David W. H. Riches1, Satoaki Matoba1, Mitsuhiko Okigaki1, Hiroaki Matsubara1
1From the Department of Cardiovascular Medicine (S.H., S.N., K.A., K.Z., E.K., A.M., A.K., S.Y., S.M., M.O., H.M.), Kyoto Prefectural University of Medicine, Japan; Department of Pathology I (Y.A.), Kansai Medical University, Osaka, Japan; Internal Medicine-1 (K.N., K.I.), National Defense Medical College, Saitama, Japan; and Department of Pediatrics (D.W.H.R.), National Jewish Medical and Research Center, Denver, Colo.
Tóm tắt
Rationale
:
It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1β has also been shown to induce cardiomyocyte hypertrophy. Thus, the role of IL-1 in the heart remains to be determined.
Objective
:
We studied the role of hypertrophy signal-mediated IL-1β/insulin-like growth factor (IGF)-1 production in regulating the progression from compensative pressure-mediated hypertrophy to heart failure.
Methods and Results
:
Pressure overload was performed by aortic banding in IL-1β–deficient mice. Primarily cultured cardiac fibroblasts (CFs) and cardiac myocytes (CMs) were exposed to cyclic stretch. Heart weight, myocyte size, and left ventricular ejection fraction were significantly lower in IL-1β–deficient mice (20%, 23% and 27%, respectively) than in the wild type 30 days after aortic banding, whereas interstitial fibrosis was markedly augmented. DNA microarray analysis revealed that IGF-1 mRNA level was markedly (≈50%) decreased in the IL-1β–deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1β and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1β–deficient CFs. IL-1β released by stretch is at a low level unable to induce IL-6 but sufficient to stimulate IGF-1 production. Promoter analysis showed that stretch-mediated IL-1β activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1β deficiency markedly increased c-Jun N-terminal kinase (JNK) and caspase-3 activities and enhanced myocyte apoptosis and fibrosis, whereas replacement of IGF-1 or JNK inhibitor restored them.
Conclusions
:
We demonstrate for the first time that pressure-mediated hypertrophy and mechanical stretch generates a subinflammatory low level of IL-1β, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis.
