Pressure-Mediated Hypertrophy and Mechanical Stretch Induces IL-1 Release and Subsequent IGF-1 Generation to Maintain Compensative Hypertrophy by Affecting Akt and JNK Pathways

Abstract

Rationale: It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1␤ 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-1␤/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-1␤-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-1␤-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 (Ϸ50%) decreased in the IL-1␤-deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1␤ and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1␤-deficient CFs. IL-1␤ 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-1␤ activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1␤ 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-1␤, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis. (Circ Res. 2009;105:1149-1158.)Key Words: interleukin-1 Ⅲ insulin-like growth factor-1 Ⅲ Akt Ⅲ JNK Ⅲ hypertrophy C ardiac hypertrophy is defined by augmentation of the ventricular mass against hemodynamic loads and upregulates contractile capacity and reduces ventricular wall stress, 1 whereas the capacity of this compensation is limited, and stronger and longer pressure overload induces pathological cardiac remodeling with left ventricular (LV) dilatation. 1 Pathological cardiac remodeling is associated with production of the extracellular matrix and causes increased signals of myocyte apoptosis. 2 Receptor tyrosine kinase, such as insulin-like growth factor (IGF)-1 receptor is involved in not only physiological hypertrophy 3 but also compensated hypertrophy after pressure overload. 4 IGF-1 promotes myocardial hypertrophy by activating phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt. 5,6 In addition, mitogenactivated protein kinase 7 acts as downstream molecules to promote hypertrophy.Overexpression of G protein-coupled 7-transmembrane receptors in the heart induced cardiac remodeling, resulting in he...

Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling

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The NAMPT Promoter Is Regulated by Mechanical Stress, Signal Transducer and Activator of Transcription 5, and Acute Respiratory Distress Syndrome–Associated Genetic Variants

“…STATs are recognized as activated by mechanical stretch (21), and we recently reported mechanical stress-mediated increased promoter activity within the HMGB1 gene as STAT3 dependent (22). CS significantly increases JAK2/STAT5 phosphorylation (23) and STAT5 translocation to the nucleus (24). Leveraging in silico information generated by predictions from Genomatix, UCSC Genome Browser (GRCh37/hg19) (25), and previous reports (8), we identified transcription factor-binding sites for STAT5 and determined that STAT5 exerts critical positive regulatory control in NAMPT responses to mechanical stretch.…”

Role of Apoptosis Signal-Regulating Kinase-1-c-Jun NH2-Terminal Kinase-p38 Signaling in Voltage-Gated K+Channel Remodeling of the Failing Heart: Regulation by Thioredoxin

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