Ritonavir stimulates foam cell formation by activating PKC

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Pharmacology

Background:

• Alpha-subtype protein kinase C (PKCα) plays a role in cardiovascular disease.
• Ritonavir (RTV), a human immunodeficiency virus (HIV) protease inhibitor, is known to induce atherosclerosis via PKC.
• The precise mechanism by which RTV affects PKCα and leads to pathological phenotypes remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which Ritonavir (RTV) interacts with alpha-subtype protein kinase C (PKCα).
• To investigate the role of RTV in inducing foam cell formation and PKCα plasma membrane translocation.
• To provide insights into the PKC-dependent induction of atherosclerosis by HIV protease inhibitors.

Main Methods:

• Primary mouse peritoneal macrophages were utilized.
• Oil Red O staining and immunofluorescence microscopy were performed.
• Computational modeling and in vitro kinase activity assays were conducted.
• Western blot analysis was employed to assess protein expression.

Main Results:

• Ritonavir (RTV) induced foam cell formation and PKCα plasma membrane translocation in macrophages, similar to phorbol-12-myristate-13-acetate (PMA).
• Computational modeling showed similar binding patterns of RTV and PMA to PKCα.
• In vitro studies demonstrated that RTV elevates PKC activity and up-regulates PKCα expression.

Conclusions:

• Ritonavir (RTV) directly activates alpha-subtype protein kinase C (PKCα), leading to foam cell formation and contributing to atherosclerosis.
• These findings enhance understanding of HIV protease inhibitor (PI) toxicity and cardiovascular risks.
• Further research is needed to explore the link between RTV-induced PKCα upregulation and estrogen responsiveness.