The role of autophagy in cardiovascular disease: Cross-interference of signaling pathways and underlying therapeutic targets

Abstract

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic proteins and organelles, which realizes the metabolic needs of cells and the renewal of organelles. Autophagy-related genes (ATGs) are the main molecular mechanisms controlling autophagy, and their functions can coordinate the whole autophagic process. Autophagy can also play a role in cardiovascular disease through several key signaling pathways, including PI3K/Akt/mTOR, IGF/EGF, AMPK/mTOR, MAPKs, p53, Nrf2/p62, Wnt/β-catenin and NF-κB pathways. In this paper, we reviewed the signaling pathway of cross-interference between autophagy and cardiovascular diseases, and analyzed the development status of novel cardiovascular disease treatment by targeting the core molecular mechanism of autophagy as well as the critical signaling pathway. Induction or inhibition of autophagy through molecular mechanisms and signaling pathways can provide therapeutic benefits for patients. Meanwhile, we hope to provide a unique insight into cardiovascular treatment strategies by understanding the molecular mechanism and signaling pathway of crosstalk between autophagy and cardiovascular diseases.

Keywords: autophagy; autophagy-related gene; cardiovascular disease; crosstalk; potential target; signaling pathway.

Figure 1

The autophagic process of three different forms in mammalians. (1) Macroautophagy, which is characterized by the formation of autophagosomes with a double-layer membrane structure engulfs intracellular macromolecular substances in a wrapped manner, and the autophagosome eventually fuses with lysosome to form autophagic lysosome, and the inclusion bodies are degraded by hydrolytic enzymes in lysosome. (2) Microautophagy, which is characterized by the specific organelles are directly engulfed in an invaginated manner by the deformation of lysosomal or vacuole surface, and the lysosomal membrane inwardly folds to crush the contents. (3) Chaperone-mediated autophagy (CMA), which is characterized by the specific amino acid sequence (such as KEFRQ motif) of soluble protein is identified and combined by a chaperone-dependent protein (such as HSPA8 complex), and transfer it to lysosomes via the receptor LAMP2A on the lysosomal membrane, so as to allow misfolded proteins to undergo defolding and complete degradation by hydrolytic enzymes in lysosome.

Figure 2

Main mechanism of autophagy in mammals and target genes for treating cardiovascular diseases. The main mechanism is that ATG protein forms five functional groups (indicated in the red box). (1) ULK1 complex, composing of FIP200, ULK1, ATG13 and ATG101, which the mTOR complex of negative regulation. (2) BECLIN1-III PI3K complex, composing of BECLIN-1, VPS34, P115, AMBRA1 and ATG14 control the nucleation phase of autophagy. (3) Two full sample combination systems (ATG12-ATG5 and LC3 systems), which regulates the structure of autophagic precursor and autophagic body. (4) WIPI1/2 and ATG2 complexes control the extending autophagosomal membrane. (5) ATG9 retrieval complex, which the only multi-hop transmembrane protein involved in vesicle transport.

Figure 3

Molecular mechanism of mitochondrial autophagy regulation can be divided into two types: ubiquitin-dependent mitochondrial autophagy (including PINK1 and Parkin) and ubiquitin-independent mitochondrial autophagy (including BNIP3, NIX, FUNDC1, PHB2, cardiolipin and so on). (1) BNIP3, FUNDC1, and NIX are all located on the outer membrane of mitochondria and can bind directly to LC3-mediated mitochondrial autophagy via the domain of LC3 interaction (LIR). (2) BNIP3 can also inhibit the proteolysis of PINK1, so as to cause the accumulation of PINK1 on the outer mitochondrial membrane, thereby promoting PINK1/Parkin-mediated mitochondrial autophagy. (3) Under the condition of non-stress, FUNDC1 is phosphorylated by protein kinase CK2α in the region of Ser-13 and phosphorylated by protein kinase SRC in the region of Tyr-18, so as to inhibit the interaction of LC3 with FUNDC1, thereby preventing the occurrence of mitochondrial autophagy. (4) Under the condition of mitochondrial membrane potential loss or hypoxia, protein phosphatase PGAM5 can interact with FUNDC1 to prevent CK2α and SRC kinase to combin with FUNDC1, resulting in the dephosphorylation of FUNDC1, so as to enhance the interaction between FUNDC1 and LC3, and induce mitochondrial autophagy. (5) As an important receptor for mitochondrial autophagy, the inner mitochondrial membrane protein PHB2 can mediate mitochondrial autophagy via the domain of LIR, and bind to the autophagic membrane-related protein LC3 during the process of mitochondrial depolarization and proteasome-dependent outer membrane rupture, which is closely associated with the PINK1/Parkin signaling pathway. (6) Cardiolipin (CL), as a phospholipid in the inner mitochondrial membrane, can be externalized to the outer mitochondrial membrane when mitochondria are damaged, while the redistribution of CL and its interaction with LC3 initiate a signaling cascade and mediate mitochondrial autophagy.

Figure 4

Regulation of cross- interference between autophagy and main signaling pathways in cardiovascular disease. (1) NF-κB pathway of IKKα/β and NF-κB induces autophagy by increasing the expression levels of autophagy-related proteins, such as Beclin-1. (2) Growth factors (including EGF, IGF and VEGF) promote autophagy by modulating the autophagic process of JNK/c-Jun, Ras/Raf/MEK/ERK and the PI3K/Akt. (3) p53 pathway: Autophagy is also mediated by the nuclear p53 activity, which is a transcribed factor under stressful conditions (such as ultraviolet rays, etc.). p53 induces the classic autophagic pathway mainly through PI3K/Akt/mTOR, AMPK/mTOR and ULK1 complex. (4) PI3K/Akt/mTOR and AMPK/mTOR receptor tyrosine kinases promote the transformation of PIP2 into PIP3 and the activation of PI3K. PTEN-induced dephosphorylation of PIP3 activates the AKT signal negatively regulated by PI3K. Amino acids and nutrient-rich conditions can initiate the activity of mTORC1 signal. By contrast, starvation and oxidative stress can inhibit the activity of mTORC1 signal and induce autophagy. (5) Wnt-β-catenin pathway: This pathway causes the activation and nuclear recruitment of β-catenin protein, so as to directly regulating autophagy.