Abstract
Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2), however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2) was involved in the process. We found that angiotensin II (Ang-II)-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA), or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB) induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II.
Highlights
Pressure overload-induced cardiac hypertrophy is mediated partly by activation of Janus kinase 2(Jak2) [1,2]
In order to test the role of Jak2 and histone deacetylase 2 (HDAC2) in cardiac hypertrophy response, siRNA strategy was utilized to selectively knockdown Jak2 or HDAC2 in H9c2 cardiomyocytes
In H9c2 cells, which was significantly inhibited by Jak2 or HDAC2 siRNA knockdown (Figure 1E–G)
Summary
Pressure overload-induced cardiac hypertrophy is mediated partly by activation of Janus kinase 2(Jak2) [1,2]. Pressure overload-induced cardiac hypertrophy is mediated partly by activation of Janus kinase 2. Under biochemical and/or mechanic stresses, cardiac Jak is activated mainly through the increased circulating angiotensin II (Ang-II) [3,4]. Treatment with the Jak inhibitor AG-490 prevented the hypertrophic response, indicating that Jak is important in the development of cardiac hypertrophy [5]. Recent studies show that transverse aorta binding (AB)-induced cardiac hypertrophy is associated with increased expression/activity of histone deacetylases (HDACs) [2]. Studies demonstrated that Trichostatin-A (TSA), a HDAC2 inhibitor, attenuated the development of cardiac hypertrophy [10,11]. We found that HDAC2 might be a downstream effector of Jak to mediate cardiac hypertrophic response
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