Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Abstract

Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Carboxyl‐Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway

“…Intriguingly, PTEN33 and CTMP exert the same effect in pathological cardiac hypertrophy induced by AngII. Except for CTMP, many molecules have been demonstrated to play crucial roles on cardiac remodeling induced by pressure overload by regulating AKT signaling 4, 35, 36, 37, 38, 39…”

“…AB was performed to induce cardiac hypertrophy by pressure overload, as previously described 4, 21. In brief, the mice (males; aged 8–10 weeks; weight, 24–27 g) were anesthetized with sodium pentobarbital via an intraperitoneal injection until the toe pinch reflex disappeared.…”

“…PBS containing 0.03% trypsin and 0.04% collagenase type II was used to isolate primary neonatal rat cardiomyocytes (NRCMs) from the hearts of 1‐ to 2‐day‐old Sprague‐Dawley rats, as described 4, 21. After removing fibroblasts by a differential attachment technique, NRCMs were seeded at a density of 2×10 5 cells per well onto 6‐well culture plates coated with gelatin in plating medium consisting of DMEM/F12 (C11330, Gibco) supplemented with 10% fetal bovine serum, bromodeoxyuridine (0.1 mmol/L, to inhibit the proliferation of fibroblasts), and penicillin/streptomycin.…”

“…However, prolonged stimulation induces a shift from compensated hypertrophy to decompensated hypertrophy, which directly leads to cardiac dysfunction, heart failure, and even sudden death 2. Thus, pathological cardiac hypertrophy is a crucial predisposing factor for cardiovascular events and is the leading cause of cardiac morbidity and mortality globally 3, 4. Multiple signaling pathways, including the mitogen‐activated protein kinase (MAPK) pathway, the phosphatidylinositol 3‐kinase/protein kinase B (AKT) pathway, and the protein kinase C pathway, have been identified in the initiation and development of pathological cardiac hypertrophy 5, 6, 7.…”

A Disintegrin and Metalloprotease‐22 Attenuates Hypertrophic Remodeling in Mice Through Inhibition of the Protein Kinase B Signaling Pathway

“…ADAM22‐transgenic C57BL/6J mice were established for cardiac‐specific conditional overexpression of ADAM22 using a standard protocol 18. Briefly, the full length of cDNA for mouse ADAM22 was obtained by polymerase chain reaction (PCR).…”