Low Levels of Low-Density lipoprotein-C Associated With Proprotein Convertase Subtilisin Kexin 9 Inhibition Do Not Increase the Risk of Hemorrhagic Transformation

Stroke. 2014 Oct;45(10):3086-8. doi: 10.1161/STROKEAHA.114.005958. Epub 2014 Aug 14.

Abstract

Background and purpose: Low levels of low-density lipoprotein-cholesterol (LDL-C) are suspected to be associated with a risk of hemorrhagic transformation after ischemic stroke. We assessed the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice with low levels of LDL-C resulting from proprotein convertase subtilisin kexin 9 (PCSK9) deficiency.

Methods: PCSK9-/- and PCSK9+/+ mice were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays. PCSK9-/- and PCSK9+/+ mice (n=15 per group) were subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous hemorrhagic transformation was assessed by quantification of hemoglobin in ischemic tissue. In vitro, a cell model of blood-brain barrier was used to test endothelial barrier integrity in response to decreasing concentrations of LDL-C from 1 to 0.25g/L in ischemia/reperfusion conditions.

Results: PCSK9-/- mice had lower LDL-C, high-density lipoprotein-cholesterol, and total cholesterol levels than PCSK9+/+ mice before and after 1 month on the high-fat/high-cholesterol diet. Hemoglobin concentration in ischemic cerebral tissue was not different between PCSK9-/- and PCSK9+/+ mice (31.5 [18.9-60.1] and 32.8 [14.7-69.9] ng/mg protein, respectively; P=0.81). Infarct volume was also similar in both groups (P=0.66). Incubation of human cerebral endothelial cells with decreasing concentrations of LDL-C under ischemia/reperfusion conditions did not alter blood-brain barrier permeability.

Conclusions: Low levels of LDL-C did not increase the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice. Our observations suggest that PCSK9 inhibition, leading to LDL-C lowering, should not increase hemorrhagic complications after acute ischemic stroke.

Keywords: PCSK9 protein; hemorrhage; low-density lipoprotein cholesterol; mice; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Cell Line
  • Cerebral Hemorrhage / epidemiology*
  • Cerebral Hemorrhage / metabolism
  • Cholesterol, LDL / blood*
  • Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors*
  • Proprotein Convertases / deficiency
  • Reperfusion Injury / complications
  • Reperfusion Injury / metabolism
  • Risk Factors
  • Serine Endopeptidases / deficiency
  • Stroke / complications*
  • Stroke / metabolism

Substances

  • Cholesterol, LDL
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases