Autocrine effects of PCSK9 on cardiomyocytes

Basic Res Cardiol. 2020 Nov 10;115(6):65. doi: 10.1007/s00395-020-00824-w.


Proprotein convertase subtilisin kexin type 9 (PCSK9) is in the focus of cardiovascular research due to its role in hepatic low density lipoprotein (LDL) clearance. However, extrahepatic expression of PCSK9 such as in cardiomyocytes and its regulation by oxidized LDL (oxLDL) put notion on extrahepatic effects of PCSK9 as well. This study was aimed to reveal the role of PCSK9 in oxLDL-dependent regulation of cardiomyocyte function. Adult rat and mouse ventricular cardiomyocytes and isolated perfused hearts were used. OxLDL was applied to increase PCSK9 expression in cardiomyocytes. Cell function was analyzed by load-free cell shortening as well as left ventricular developed pressure of isolated hearts. OxLDL decreased shortening in wild-type-derived mouse cardiomyocytes but not in those isolated from PCSK9 knockout mice. Overexpression of human PCSK9 in rat cardiomyocytes reduced shortening in the absence of oxLDL. Addition of recombinant PCSK9 mimicked these effects. In cardiomyocytes, oxLDL induced PCSK9 release into the supernatant. Inhibition of PCSK9 by Pep 2-8 or alirocumab attenuated the oxLDL-induced loss of cardiomyocyte shortening. Cardiomyocytes express surfeit locus protein 4 (SURF-4), a protein required for PCSK9 secretion in human embryonic kidney cells (HEK 293 T), and silencing of SURF-4 reduced the oxLDL effects on cardiomyocytes. In isolated perfused rat hearts PCSK9 inhibition by alirocumab improved the function. In addition, left ventricular function of isolated hearts from PCSK9 knockout mice was increased under basal conditions as well as at 10 min and 120 min of reperfusion following 45 min of ischemia. Collectively, the data show that cardiomyocytes express and release PCSK9 that acts in an autocrine way on cardiomyocytes and impairs their function.

Keywords: Cardiac function; Cardiomyocytes; Cardiovascular disease; PCSK9; oxLDL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Autocrine Communication* / drug effects
  • Hep G2 Cells
  • Humans
  • Isolated Heart Preparation
  • Lipoproteins, LDL / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Contraction
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • PCSK9 Inhibitors
  • Proprotein Convertase 9 / genetics
  • Proprotein Convertase 9 / metabolism*
  • Rats, Wistar
  • Serine Proteinase Inhibitors / pharmacology
  • Signal Transduction
  • Ventricular Function, Left
  • Ventricular Pressure


  • Antibodies, Monoclonal, Humanized
  • Lipoproteins, LDL
  • Membrane Proteins
  • PCSK9 Inhibitors
  • Serine Proteinase Inhibitors
  • Surf4 protein, mouse
  • oxidized low density lipoprotein
  • PCSK9 protein, human
  • PCSK9 protein, rat
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • alirocumab