Sex-Specific Effects of the Nlrp3 Inflammasome on Atherogenesis in LDL Receptor-Deficient Mice

Shuang Chen; Janet L Markman; Kenichi Shimada; Timothy R Crother; Malcolm Lane; Amanda Abolhesn; Prediman K Shah; Moshe Arditi

doi:10.1016/j.jacbts.2020.03.016

Sex-Specific Effects of the Nlrp3 Inflammasome on Atherogenesis in LDL Receptor-Deficient Mice

JACC Basic Transl Sci. 2020 May 20;5(6):582-598. doi: 10.1016/j.jacbts.2020.03.016. eCollection 2020 Jun.

Authors

Shuang Chen¹, Janet L Markman¹, Kenichi Shimada¹, Timothy R Crother¹, Malcolm Lane¹, Amanda Abolhesn¹, Prediman K Shah^{1

2}, Moshe Arditi^{1

2}

Affiliations

¹ Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, California.
² Division of Cardiology, Department of Medicine, Oppenheimer Atherosclerosis Research Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Abstract

In the Ldlr ^-/- mouse model of atherosclerosis, female Nlrp3 ^-/- bone marrow chimera and Nlrp3 ^-/- mice developed significantly smaller lesions in the aortic sinus and decreased lipid content in aorta en face, but a similar protection was not observed in males. Ovariectomized female mice lost protection from atherosclerosis in the setting of NLRP3 deficiency, whereas atherosclerosis showed a greater dependency on NLRP3 in castrated males. Thus, castration increased the dependency of atherosclerosis on the NLRP3 inflammasome, suggesting that testosterone may block inflammation in atherogenesis. Conversely, ovariectomy reduced the dependency on NLRP3 inflammasome components for atherogenesis, suggesting that estrogen may promote inflammasome-mediated atherosclerosis.

Keywords: ACVD, atherosclerotic cardiovascular disease; BM, bone marrow; CAS, castration; ER, estrogen receptor; FLICA, fluorescent labeled inhibitors of caspases; HFD, high-fat diet; IL, interleukin; IL-1β; NLRP3 inflammasome; NLRP3, nucleotide-binding domain and leucine-rich repeat containing (NLR) protein3; OVX, ovariectomy; atherosclerosis; sex.

Abstract

Grants and funding