Effects of castration on atherosclerosis in Yucatan minipigs with genetic hypercholesterolemia

PLoS One. 2020 Jun 5;15(6):e0234131. doi: 10.1371/journal.pone.0234131. eCollection 2020.

Abstract

Background: Low plasma testosterone, either spontaneous or as a result of androgen deprivation therapy for prostate cancer, is associated with an increased risk of cardiovascular events. The underlying mechanism in humans is not understood. Experimental studies in mice have shown that castration facilitates atherogenesis and may increase signs of plaque vulnerability. Pigs used for translational atherosclerosis research have frequently been castrated for practical or commercial reasons, but the effect of castration on atherosclerosis has never been systematically evaluated in pigs.

Objective: To study the effect of castration on atherosclerotic plaque burden and type in genetically modified minipigs with hypercholesterolemia.

Methods: Newborn male Yucatan minipigs with transgenic overexpression of a human gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 were randomized to undergo orchiectomy (n = 8) or serve as controls (n = 6). Minipigs were started on high-fat diet at 3 months of age and the amount and composition of atherosclerotic lesions were analyzed at 12 months of age. Plasma lipid profiles and behavioral parameters were also assessed.

Results: Plasma lipids were slightly affected to a more atherogenic profile by orchiectomy, but atherosclerotic lesion size was unaltered in the LAD, thoracic aorta, abdominal aorta, and iliac arteries. The distribution of lesion types (xanthomas, pathological intimal thickening and fibroatheromas) were also not statistically different between groups in any of the examined vascular territories. The abdominal aorta developed the most advanced stages of disease with reproducible fibroatheroma formation, and here it was found that the area of necrotic core was significantly increased in orchiectomized pigs compared with controls. Orchiectomy also reduced aggressive behavior.

Conclusions: Castration does not alter the burden of atherosclerosis in hypercholesterolemic Yucatan minipigs, but may increase necrotic core area in fibroatheromas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Aorta / pathology
  • Atherosclerosis / complications
  • Atherosclerosis / pathology*
  • Diet, High-Fat
  • Disease Models, Animal
  • Humans
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / pathology*
  • Iliac Artery / pathology
  • Lipids / blood
  • Male
  • Necrosis
  • Orchiectomy
  • Proprotein Convertase 9 / genetics
  • Proprotein Convertase 9 / metabolism
  • Swine
  • Swine, Miniature
  • Testosterone / blood

Substances

  • Lipids
  • Testosterone
  • PCSK9 protein, human
  • Proprotein Convertase 9

Grant support

The study was funded by a grant from the Danish Independent Research Council (Sapere Aude Programme, 4004-00459B) and a fellowship from The Graduate School of Health, Aarhus University, Aarhus, Denmark. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.