The role of heat shock proteins in atherosclerosis

Abstract

Atherosclerosis is a chronic, multifactorial disease that starts in youth, manifests clinically later in life, and can lead to myocardial infarction, stroke, claudication, and death. Although inflammatory processes have long been known to be involved in atherogenesis, interest in this subject has grown in the past 30-40 years. Animal experiments and human analyses of early atherosclerotic lesions have shown that the first pathogenic event in atherogenesis is the intimal infiltration of T cells at arterial branching points. These T cells recognize heat shock protein (HSP)60, which is expressed together with adhesion molecules by endothelial cells in response to classic risk factors for atherosclerosis. Although these HSP60-reactive T cells initiate atherosclerosis, antibodies to HSP60 accelerate and perpetuate the disease. All healthy humans develop cellular and humoral immunity against microbial HSP60 by infection or vaccination. Given that prokaryotic (bacterial) and eukaryotic (for instance, human) HSP60 display substantial sequence homology, atherosclerosis might be the price we pay for this protective immunity, if risk factors stress the vascular endothelial cells beyond physiological conditions.

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

“…Since then several heat shock proteins have been postulated to be involved in atherosclerosis in a pro-or anti-atherosclerotic mode, although the mechanisms have not been clearly defined [25,35,36].…”

Targeting B Cells in Atherosclerosis

“…Atherosclerosis is a distinct case compared with typical autoimmune diseases because (1) the major autoantigen oxLDL is really a modified self-antigen or neo-self-antigen and (2) the oxLDL autoantigen, rather than playing a physiological function, is pathogenic and disease causing. There are also other autoantigens involved, such as heat shock protein 60,6,7 and the impact of other autoimmune diseases in promoting atherosclerosis such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well known. 8,9 The role of T cells and interferon-γ-secreting Th1 cells, in particular, as key drivers of plaque inflammation is well documented, and experimental approaches to dampen these responses by enhancing the activity of regulatory T cells are being tested.…”

Tolerization against atherosclerosis using heat shock protein 60

“…At later stages of atherogenesis, intralesional T cells, macrophages, dendritic cells (DCs), and smooth muscle cells (SMCs) can also express HSP60, and the anti-HSP60 cellular immune reaction could therefore be perpetuated in situ. These experimentally and clinically proven findings represent the basis for the BAutoimmune Concept of Atherosclerosis^ (Wick et al 2004(Wick et al , 2014. This concept was first presented in 1992 and showed that normocholesterolemic rabbits immunized with mbHSP65 develop atherosclerotic plaques irrespective of their cholesterol levels Xu et al 1992).…”

“…Moreover, during the last two decades, we and other laboratories have identified HSP60 as one of the most important antigens in early stages of atherosclerosis Wick et al 1995Wick et al , 2004. Proof of concept for the presence of antigenic mimicry has been thoroughly investigated in different animal models and humans (Wick et al 2014).…”