Estrogen Receptor-α Mediates Gender Differences in Atherosclerosis Induced by HIV Protease Inhibitors

Abstract

As part of highly active antiretroviral therapy, protease inhibitor treatment has significantly increased the lifespan of HIV infected individuals. Many patients, however, develop negative side effects including premature atherosclerosis. We have previously demonstrated that in male low-density lipoprotein receptor (LDL-R) null mice, HIV protease inhibitors induce atherosclerotic lesions and cholesterol accumulation in macrophages in the absence of changes in plasma lipid levels. We determined that these increases were due to an up-regulation of the scavenger receptor, CD36. In the present study, we examined the effects of HIV protease inhibitors in female LDL-R null mice. Female mice given ritonavir and amprenavir (23 and 10 μg/mouse/day, respectively) developed fewer atherosclerotic lesions than males. Furthermore, peritoneal macrophages isolated from ritonavirtreated females had reduced levels of cholesterol accumulation as compared to males, and CD36 protein levels were increased to a significantly lesser degree in females than in males. To investigate the molecular mechanisms of this gender difference, we examined the effect of genetically removing estrogen receptor-alpha (ERα). In female mice lacking both LDL-R and ERα, the protective effect of gender was lost. Additionally, the reduced levels of cholesterol accumulation in macrophages observed in females was reversed. Furthermore, the absence of ERα resulted in increased expression of CD36 protein in a macrophage-specific manner in mice treated with ritonavir. These data demonstrate that ERα is directly involved in the regulation of cholesterol metabolism in macrophages and plays an important role in the gender differences observed in HIV protease inhibitor-induced atherosclerosis.

Association of CD36 expression and polymorphism with serum biochemical indices in Cherry Valley duck

“…For example, the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) and the cytokines oxidized low-density lipoprotein (oxLDL) and interleukin-4 (IL-4) are known to upregulate CD36 expression. Evidence has shown that HIV protease inhibitors contribute to induce CD36 expression in male mice, but have the opposite effect in female mice (Allred et al, 2006). Hepatic CD36 expression in male and female contrasts with the finding what has Allred made under hormonal and nutritional conditions (Cheung et al, 2007).…”

Terapia antirretroviral altamente eficaz para infecção pelo vírus da imunodeficiência humana aumenta a rigidez aórtica

“…A study in LDL-null mice examined the effects of ritonavir and amprenavir on cholesterol accumulation in macrophages, showing that females had lowers levels than males. The protective effect was lost after genetically removing estrogen receptor-alpha 28 .…”

Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention

“…Depending on the experimental system used, the mechanisms of CD36 over-expression by ritonavir involves protein kinase C (PKC) (Bradshaw et al, 2006;Dressman et al, 2003), the estrogen receptor alpha (ERa) (Allred et al, 2006), as well as cellular proteasome inhibition in human THP-1 monocytes (Munteanu et al, 2004a(Munteanu et al, , 2005. In ritonavir-treated mouse macrophages, PKC activation and increased PPARc and CD36 expression are reverted by the nucleoside reverse transcriptase inhibitor didanosine via increased ubiquitination and degradation of PKCa, whereas a-tocopherol is without effect in this in vivo model (Bradshaw et al, 2006;Dressman et al, 2003).…”