SHP-2 specific deletion in macrophages accelerates pathological cardiac hypertrophy through promoting IRE1α-XBP1s pathway regulated by IL-6 secretion

Abstract

SHP-2 is a pervasively Src homology 2 (SH2) domain-containing protein tyrosine phosphatase (PTP) and its specific deletion in macrophages can promote the IL-6 secretion in the pathophysiological process of cardiac hypertrophy. To elucidate the mechanism, AngII infused Lyz-2-Cre/SHP-2flox/flox mice and SHP-2 MφCKO wild-type (SHP-2+/+) mice were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Echocardiographic scans showed that left ventricular (LV) end-diastolic dimension and left ventricular systolic volume were significantly increased in SHP-2flox/flox group, implying that TAC-induced SHP-2flox/flox can induce LV hypertrophy and damage cardiac function. In addition, IHC analysis and Western blotting demonstrated that SHP-2flox/flox obviously elevated the expression of α-SMA, collagen, circulating macrophage numbers and positive areas and expression level of IL-6 in vitro. Moreover, SHP-2flox/flox positively regulated IRE1α-XBP-1 activation, whereas the expression levels of NF-κB did not differ between SHP-2flox/flox and SHP-2+/+ mice. It was also confirmed that the increased expression levels of IL-6, p-IRE1α, and XBP1s in SHP-2flox/flox mice were markedly reversed by 3,6-DMAD hydrochloride (an inhibitor of the IRE1α-XBP1s pathway). These results demonstrated that SHP-2flox/flox promotes IL-6 secretion via the IRE1α-XBP1s pathway rather than NF-κB signaling pathway in the development of cardiac hypertrophy.