Lysosome Function in Cardiovascular Diseases

Abstract

The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as proteases, nucleases, and phosphatases that are able to degrade extracellular and intracellular components. It is well known that lysosomes act as a center for degradation and recycling of large numbers of macromolecules delivered by endocytosis, phagocytosis, and autophagy. Lysosomes are recognized as key organelles for cellular clearance and are involved in many cellular processes and maintain cellular homeostasis. Recently, it has been shown that lysosome function and its related pathways are of particular importance in vascular regulation and related diseases. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and vascular physiological and pathophysiological activities in arterial smooth muscle cells (SMCs) and endothelial cells (ECs). Sphingolipids-metabolizingenzymes in lysosomes play critical roles in intracellular signaling events that influence cellular behavior and function in SMCs and ECs. The focus of this review will be to define the mechanism by which the lysosome contributes to cardiovascular regulation and diseases. It is believed that exploring the role of lysosomal function and its sphingolipid metabolism in the initiation and progression of vascular disease and regulation may provide novel insights into the understanding of vascular pathobiology and helps develop more effective therapeutic strategies for vascular diseases.

Keywords: Lysosome; Smooth Muscle Cells; Exosomes; Sphingolipids; Vascular Calcification.

Fig. 1.

Phenotype switch of VSMCs and exosome secretion. Upon various stimuli VSMCs may be subjected to oxidative stress, ER stress, increased calcium (Ca²⁺) and phosphate (P_i) levels, upregulation of osteogenic markers and phenotype change. Under such conditions SMCs may produce and release large number of exosomes (30–100 nm) which are composed of lipid bilayer membrane and usually carries lipids, DNA, RNA (Non-coding RNAs such as mRNA, miRNA, LncRNA, and circRNA) and proteins including annexins, alkaline phosphatase, oxidant stress proteins and surface membrane proteins etc. VSMCs: Vascular smooth muscle cells; ER: Endoplasmic Reticulum.

Fig. 2.

Cross talk between ECs and SMCs during atherosclerosis. Various danger factors act on ECs which may induce lysosomal trafficking and fusion to cell membrane resulting in ceramide production via activation of ASMase leading to the formation of MR-Nox redox signalosomes. Nox-derived O^2.− lead to redox regulation of vascular endothelial and smooth muscle function which may lead to endothelial injury promoting atherosclerosis. SMCs switch from the ‘contractile’ to the ‘synthetic’ phenotype and migrate from the vessel’s media into the intima. Atherosclerotic plaques are characterized by an accumulation of lipids, cholesterol loaded macrophage-derived foam cells, chemokines and cytokines. SMCs: Smooth muscle cells; CER: Ceramide; Nox: NADPH oxidase; SM: Sphingomyelin; ASMase: Acid Sphingomyelinase; LR: Lipid Rafts.

Fig. 3.

Schematic model demonstrating lysosomal sphingolipid-mediated exosome secretion from SMCs during vascular calcification. Lysosomal sphingolipid metabolism regulates TRPML1-mediated Ca²⁺ release from lysosomes, which controls lysosome trafficking and fusion with MVBs via, and thereby controlling the fate of these MVBs. Due to deficient lysosome trafficking or fusion to MVBs, MVBs fuse with the plasma membrane, which is associated with exosome excretion in arterial SMCs during vascular calcification. SMCs: Smooth muscle cells; CER: Ceramide; SM: Sphingomyelin; ASM: Acid Sphingomyelinase; AC: Acid Ceramidase; TRPML1: Lysosomal transient receptor potential mucolipin 1; MVB: Multivesicular Body.