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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.
Highlights
Pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor
The suppressor of IKKe (SIKE) mRNA level was significantly reduced in human hearts with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) compared with normal hearts (Fig. 1a), as well as in aortic banding (AB)-challenged hypertrophic mouse hearts compared with sham-operated hearts (Fig. 1b)
Human and mouse hypertrophic hearts showed significantly decreased SIKE protein with remarkably increased hypertrophic marker proteins, that is, atrial natriuretic peptide (ANP) and b-myosin heavy chain (b-MHC; Fig. 1c–e). This decrease in the SIKE level in hypertrophic cardiac cells was confirmed in cultured neonatal rat cardiomyocytes (NRCMs) stimulated with either angiotensin II (Ang II) (1 mM) or phenylephrine (PE; 100 mM) for 48 h to induce hypertrophy
Summary
Pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. We demonstrate that suppressor of IKKe (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. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys 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. Much less is known about how cardiac hypertrophy is suppressed These negative regulators could be of significant therapeutic value and could facilitate the development of gene-based therapies for the treatment of cardiac hypertrophic pathologies[11,12]. Our mechanistic investigations emphasize the role of TBK1-AKT cascades during SIKE-regulated cardiac hypertrophy
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