Cardiac-specific ITCH overexpression ameliorates septic cardiomyopathy via inhibition of the NF-κB signaling pathway

Septic cardiomyopathy is a common complication of septic shock and organ dysfunction. ITCH is a HECT (homologous to the E6-AP carboxyl-terminus)-type ubiquitin E3 ligase that plays a critical role in inflammatory suppression. Herein, we focused on the interaction between ITCH and key regulators of nuclear factor-κB (NF-κB), such as tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-β activated kinase 1 (TAK1), and examined the impact of ITCH on the development of septic cardiomyopathy.

In H9C2 cardiomyocytes, ITCH protein expression decreased in response to lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα). The protein interactions of ITCH with TRAF6 and TAK1 were confirmed by immunoprecipitation in vitro and in vivo. Based on overexpression and knockdown studies of ITCH in H9C2 cardiomyocytes, ITCH regulates the phosphorylation of NF-κB and subsequent interleukin 6 (IL-6) expression in response to LPS and TNFα stimulation. LPS was intraperitoneally injected into transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type (WT) mice. Compared with WT mice, phosphorylation of NF-κB and subsequent IL-6 expression were inhibited in ITCH-Tg mice. Cardiac systolic dysfunction after LPS administration was ameliorated in ITCH-Tg mice, and the survival rate was higher in ITCH-Tg mice than in WT mice.

ITCH interacts with TRAF6 and TAK1 in cardiomyocytes and improves cardiac function and survival rates in septic cardiomyopathy by suppressing the NF-κB pathway.