CDC20 regulates cardiac hypertrophy via targeting LC3-dependent autophagy

Abstract

Rationale: Sustained cardiac hypertrophy often leads to heart failure (HF). Understanding the regulation of cardiomyocyte growth is crucial for the treatment of adverse ventricular remodeling and HF. Cell division cycle 20 (CDC20) is an anaphase-promoting complex activator that is essential for cell division and tumorigenesis, but the role of CDC20 in cardiac hypertrophy is unknown. We aimed to test whether CDC20 participates in the regulation of pathological cardiac hypertrophy and investigate the underlying mechanism in vitro and in vivo.Methods: Male C57BL/6 mice were administered a recombinant adeno-associated virus serotype 9 (rAAV9) vector expressing CDC20 or a siRNA targeting CDC20 and their respective controls by tail intravenous injection.Results: Microarray analysis showed that CDC20 was significantly upregulated in the heart after angiotensin II infusion. Knockdown of CDC20 in cardiomyocytes and in the heart reduced cardiac hypertrophy upon agonist stimulation or transverse aortic constriction (TAC). Conversely, enforced expression of CDC20 in cardiomyocytes and in the heart aggravated the hypertrophic response. Furthermore, we found that CDC20 directly targeted LC3, a key regulator of autophagy, and promoted LC3 ubiquitination and degradation by the proteasome, which inhibited autophagy leading to hypertrophy. Moreover, knockdown of LC3 or inhibition of autophagy attenuated Ang II-induced cardiomyocyte hypertrophy after deletion of CDC20 in vitro.Conclusions: Our study reveals a novel cardiac hypertrophy regulatory mechanism that involves CDC20, LC3 and autophagy, and suggests that CDC20 could be a new therapeutic target for patients with hypertrophic heart diseases.

The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation

“…ardiac-specific deficiency of ATG5 results in left ventricular hypertrophy, dilatation, and contractile dysfunction and mitochondrial misalignment and aggregation at 1 week after pressure overload ( 18 ) However, the role of autophagy in cardiac hypertrophy requires further study. our data revealed that 2, 5 6 β5i KO but further enhanced by overexpression of β5i in primary cardiomyocytes and in the heart (Figs. 2, F and G, 5E, and 6E).…”

“…Subjection to TAC for 2 to 4 weeks usually induces the expression of ATG5, ATG6/Beclin-1, ATG16L1, and LC3-II, leading to the induction of autophagy in the heart ( 21 , 22 ). asic autophagy is required for the physiological maintenance of cellular homeostasis, but excessive autophagy or insufficient autophagy may influence cell survival, cardiac hypertrophy, and HF ( 24 , 25 ). To date, the beneficial role of autophagy in hypertrophic remodeling remains controversial.…”

“…In addition, cysteine proteases, such as calpain, cleave ATG5, leading to the inhibition of ATG5 ( 42 ). Notably, our recent results showed that the E3 ligase CDC20 associates with LC3 and promotes the ubiquitination and degradation of LC3 by the proteasome, thereby attenuating autophagy in cardiomyocytes ( 23 ), indicating that ubiquitination is an important mechanism mediating the induction of autophagy in cardiomyocytes. The present study provided further novel evidence that β5i interacts with ATG5 and promotes the degradation of ubiquitinated ATG5, resulting in the inhibition of autophagy and cardiac hypertrophy (Fig.…”

Inhibiting SLC26A4 reverses cardiac hypertrophy in H9C2 cells and in rats

“…Adaptation of protein turnover is a key process of cardiac hypertrophy, which is the balance between protein synthesis and degradation (Ullrich et al, 2019). The main mechanism controlling protein degradation is the ubiquitin-proteasome system, which is important for many cellular processes, including apoptosis (Xie et al, 2018). We showed that siRNA-SLC26A4 treatment could promote apoptosis of cardiomyocytes induced by PE, indicating that inhibiting SLC26A4 could remodel cardiac structure after cardiac hypertrophy through the induction of apoptosis.…”

“…It has been found that changes in autophagosome-lysosomal pathway activity have key pathogenic effects in cardiac hypertrophy (Ba et al, 2019). Autophagy at the normal levels protects cardiomyocytes from environmental stimuli, but autophagy imbalance can lead to cardiac hypertrophy (Xie et al, 2018). Therefore, cardiomyocyte autophagy plays an important role in maintaining myocardial function.…”