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Figure 2 Comparison of the interleukin (IL)-6–glycoprotein 130 (gp130)–Janus kinase (JAK)–signal transducer and activator of transcription 3 (STAT3) signal cascade in end-stage failing human hearts with the cardiac phenotype of mice harboring systemic or cardiac-restricted knockouts in this cascade. The left side indicates the alterations in the IL-6–gp130–JAK–STAT3 cascade in end-stage human dilated cardiomyopathy in comparison with normal myocardium: Serum levels of IL-6 are upregulated and myocardial IL-6 protein levels are reduced; gp130 protein levels are not altered, but their activation stage (tyrosine phosphorylation) is enhanced; JAK2 activation (tyrosine phosphorylation) is diminished with no alteration in protein expression; STAT3 is reduced at both the protein level and the activation stage (tyrosine phosphorylation) (60–62). The right side summarizes the cardiac phenotypes of mice with mutations in the IL-6–gp130–JAK–STAT3 signaling cascade. Mice with systemic deletion of IL-6 (IL-6^–/–) have no apparent cardiac phenotype at baseline or after myocardial infarction (69); mice with cardiac-restricted deletion of gp130 (-myosin heavy chain [MHC]-Cre^tg/–; gp130^flox/flox) appear normal at baseline but show early cardiac failure and enhanced mortality after pressure overload induced by thoracic aortic constriction (TAC) (63). Mice with cardiac-restricted deletion of STAT3 (-MHC-Cre^tg/–; STAT3^flox/flox) develop an age-related dilated cardiomyopathy (67,68) and are more susceptible to ischemic injury (67). In summary, the gp130–STAT3 cascade seems to promote hypertrophy, cardioprotection, and angiogenesis in the stressed heart (4,63–66,68).