HDAC7A adenovirus

Salt-inducible kinases (SIKs) are key regulators of cellular metabolism and growth, but their role in cardiomyocyte plasticity and the pathogenesis of heart failure is unclear. Studies here demonstrate that loss of SIK1 kinase activity protects against adverse cardiac remodeling and the pathogenesis of heart failure in rodent models and in cardiomyocytes derived from human induced pluripotent stem cells. The researchers found that SIK1 phosphorylates and stabilizes the histone deacetylase 7 (HDAC7) protein during cardiac stress, an event required for pathological cardiomyocyte remodeling. Gain- and loss-of-function studies of HDAC7 in cultured cardiomyocytes revealed that HDAC7 is a pro-hypertrophic signaling effector capable of inducing c-Myc expression, suggesting a functional deviation from the canonical MEF2 corepressor function of class IIa HDACs. Taken together, these findings reveal a previously unrecognized role for what we believe to be the SIK1/HDAC7 axis in regulating cardiac stress responses and implicate this pathway as a potential target for human heart failure.

Here, siRNA-mediated knockdown of Hdac7 in NRVMs significantly attenuated PE-induced cardiac hypertrophy and the induction of typical heart failure-related genes (Figure 1A-C). In contrast, siRNA-mediated knockdown of Hdac5 resulted in significant induction of Nppa and Nppb transcripts at baseline and after PE stimulation (Figure 1C), consistent with the role of HDAC5 as a transcriptional corepressor. After transduction of the MEF2 reporter construct into NRVMs, the results showed that Hdac7 knockdown had no effect on MEF2 transcriptional activity, while Hdac5 knockdown increased MEF2 activity (Figure 1D), further supporting the view that HDAC7 functions differently from other class IIa HDACs. In addition, the researchers infected NRVMs with an adenovirus expressing HDAC7 (Ad-HDAC7) followed by treatment with or without SIK inhibitors and PE. Under non-stimulated conditions, HDAC7 overexpression was sufficient to induce cardiomyocyte hypertrophy and the expression of Nppa, Nppb, and Myh7 compared with controls (Figure 1E-G). SIK inhibition suppressed cardiomyocyte hypertrophy (Figure 1E-G) and reduced HDAC7 protein abundance. Reconstitution of HDAC7 partially reversed the protective effects of SIK inhibition during PE-mediated stress (Figure 1E-G ).

Figure 1. Loss of HDAC7 protects against pathologic cardiac remodeling in vitro. (Hsu A, et al., 2020)