Abstract
Background/AimHypertensive cardiac hypertrophy is the leading cause of cardiac remodeling and heart failure. We recently demonstrated that the immunoproteasome, an inducible form of the constitutive proteasome, plays a critical role in regulating cardiovascular diseases. However, the role of the immunoproteasome LMP10 (β2i) catalytic subunit in the regulation of angiotensin II (Ang II)-induced cardiac hypertrophic remodeling remains unclear.MethodsWild-type (WT) and LMP10 knockout (KO) mice were infused with Ang II 1,000 ng/kg/min for 2 weeks. Blood pressure was measured using a tail-cuff system. Cardiac function and hypertrophic remodeling were examined by echocardiography and histological staining. The expression levels of genes and proteins were examined with quantitative real-time PCR and immunoblotting analysis, respectively.ResultsLMP10 mRNA and protein expression was significantly increased in Ang II-stimulated hearts and primary cardiomyocytes. Moreover, Ang II infusion for 2 weeks increased systolic blood pressure, abnormal cardiac function, hypertrophy, fibrosis, and inflammation in WT mice, which were significantly reversed in KO mice. Moreover, a marked reduction in the protein levels of insulin growth factor-1 receptor (IGF1R), glycoprotein 130 (gp130), and phosphorylated AKT, mTOR, STAT3, and ERK1/2 and an increase in the LC3II/I ratio were also observed in LMP10 KO mice compared with WT mice after Ang II infusion. In vitro culture experiments confirmed that LMP10 knockdown activated autophagy and increased IGF1R and gp130 degradation, leading to the inhibition of cardiomyocyte hypertrophy. However, inhibiting autophagy with chloroquine reversed this effect.ConclusionThe results of this study indicate that LMP10 KO attenuates Ang II-induced cardiac hypertrophic remodeling via the autophagy-dependent degradation of IGF1R and gp130, and suggests that LMP10 may be a novel therapeutic target for hypertrophic heart diseases.
Highlights
Sustained cardiac hypertrophy is associated with a significant increase in the risk for heart failure and sudden death (Frey and Olson, 2003)
These results suggest that the upregulation of LMP10 in cardiomyocytes may play a role in angiotensin II (Ang II)-infused cardiac hypertrophy
The Ang IIinduced upregulation of LMP10 inhibited the activation of autophagy, which in turn increased the stability of insulin growth factor1 receptor (IGF1R) and gp130 and subsequent development of cardiac hypertrophy
Summary
Sustained cardiac hypertrophy is associated with a significant increase in the risk for heart failure and sudden death (Frey and Olson, 2003). The pathological changes of hypertrophy are characterized by myocyte growth, fibrosis, enhanced protein synthesis, and fetal gene expression (Frey and Olson, 2003) Neurohormonal stimuli such as angiotensin II (Ang II) play important roles in the pathogenesis of cardiac remodeling in a variety of diseases (Wang et al, 2016; Wang L. et al, 2018). Increasing evidence has demonstrated that Ang II can activate G protein-coupled receptors, receptor tyrosine/serine/threonine kinases, and cytokine/growth factor receptors, thereby stimulating intracellular signal transduction pathways that play an important role in the initiation, regulation, and adaptation of cardiac hypertrophy (Frey and Olson, 2003). Strategies that modulate the expression and activation of IGF1R and gp130 may be promising approaches for the treatment of hypertrophic heart diseases
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