Palmitoylation in cardiovascular diseases: Molecular mechanism and therapeutic potential

Abstract

Cardiovascular disease is one of the leading causes of mortality worldwide, and involves complex pathophysiological mechanisms that encompass various biological processes and molecular pathways. Post-translational modifications of proteins play crucial roles in the occurrence and progression of cardiovascular diseases, among which palmitoylation is particularly important. Various proteins associated with cardiovascular diseases can be palmitoylated to enhance the hydrophobicity of their molecular subdomains. This lipidation can significantly affect some pathophysiological processes, such as metabolism, inflammation by altering protein stability, localization, and signal transduction. In this review, we narratively summarize recent advances in the palmitoylation of proteins related to cardiovascular diseases and discuss its potential as a therapeutic target.

Keywords: Cardiovascular diseases; Palmitoylation; Post-translational modifications; zDHHC.

Graphical abstract

Fig. 1

Protein palmitoylation and depalmitoylation. (A) The dynamic cycle between palmitoylation and depalmitoylation. Proteins are palmitoylated by DHHC-PATs at endoplasmic reticulum (ER) or Golgi and then transferred to membrane components. Depalmitoylases (APT1/2, PPT1/2 and ABHD17) remove palmitate acid from substrates. (B) Palmitate from palmitoyl-CoA can be thioesterified to substrate proteins (green) by zDHHC-PATs (blue) with two steps. zDHHC-PATs first undergo an autopalmitoylation at the cysteine residue on its DHHC motif. Second, the palmitate group is transferred to a specific cysteine on a substrate protein. (C) Depalmitoylases remove palmitate groups from palmitoylated substrates. Among these enzymes, APT1/2 have a hydrophobic pocket to accept palmitate group and release fatty acid from the substrate. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Palmitoylation in lipid uptake and synthesis. (A) CD36 (purple) is palmitoylated by zDHHC4 when transported from the endoplasm reticulum (ER) to Golgi. ARF6 promotes the migration of palmitoylated CD36 to the plasma membrane (PM). zDHHC5 maintains its localization on the membrane. FAs bind to CD36 in a caveolae on the plasma membrane of adipocytes. APT1 depalmitoylates CD36, initiating CD36-mediated caveolar endocytosis. The endocytosed vesicles deliver FAs to lipid droplets for storage. zDHHC11 activates ATGL and accelerates lipid breakdown and β-oxidation in lipid droplets. (B) FASN and ACLY are crucial enzymes in the synthesis of fatty acids. zDHHC6 palmitoylates transcription factor PPARγ and increases its nuclear translocation, upregulation ACLY. zDHHC23 palmitoylates PHF2 and enhances its ubiquitination degradation. And the decrease of PHF2 downregulate the ubiquitination of SREBP1c, increasing the level of FASN. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Palmitoylation functions in the cardiovascular diseases. Summary of palmitoylation involved in the progression of cardiovascular diseases. Schematic representation of (A) coronary artery diseases, (B) cardiac arrhythmia, (C) cardiomyopathy, and (D) vascular dysfunction. Proteins in blue boxes are substrates that can be palmitoylated, followed by the corresponding enzymes in parentheses. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Therapeutic strategies of palmitoylation. Key enzymes, substrate proteins, and cysteine residues are considered therapeutic targets. GNS561 binds to PPT1 competitively and 2-BP inhibits palmitoylation widely. Several chemical inhibitors, small molecule drugs and fatty acid in the diet can potentially influence palmitoylation.