The heat shock response is one of a number of cellular maintenance processes that works to keep cells functional under circumstances of stress. As the name implies, heat is one of those stresses in this case, but the heat shock response is also triggered by other stresses as well. Further, the heat shock response has a role in resolving inflammation. Researchers here note that the heat shock response is suppressed in atherosclerosis, possibly as a result of the chronic inflammation induced by the presence of senescent cells, possibly due to other mechanisms, and that this might be an important factor in the progression of the condition. The study shows that upregulating the heat shock response via heat treatment produces benefits in atherosclerotic mice, and the authors suggest this might function via reductions in cholesterol levels and reductions in inflammation.
While acute inflammatory responses evolved to protect organisms against pathogens and to provide tissue repair under sterile injuries, they are rapidly resolved by several physiological feedback systems aimed at avoiding the perpetuation of inflammation. In this sense, the heat shock (HS) response, i.e., the anti-inflammatory program mainly centered in heat shock factor-1 (HSF1)-dependent expression of heat shock proteins (HSPs) and other anti-aggregative protein chaperones, powerfully resolves acute inflammation by shutting off nuclear factor κB (NF-κB) and other downstream pro-inflammatory signals.
Nevertheless, if injuring stimuli become chronic, HSF1 expression is severely blunted and cells stop producing cardioprotective HSPs (e.g., HSP27, HSP72), which are anti-inflammatory. This is the case of many (if not all) chronic degenerative diseases of inflammatory nature. In contrast, inducers of the HS response clearly reverse vascular lesions in atherosclerotic models. However, the development of atherosclerotic lesions is also associated with the blockade of the expression and activity of sirtuin-1 (SIRT1), which, in turn, underlies both HSF1 expression and transcribing activity. Therefore, in an atherosclerotic milieu, the physiological resolution of inflammation is critically jeopardized thus contributing to foam cell formation and vascular senescence observed in atherosclerosis.
These observations led us to hypothesize that disruption of the anti-inflammatory and anti-senescent HS response pathways could underlie the perpetuation of vascular inflammation in atherosclerosis, as observed in other chronic inflammatory diseases, and that in vivo heat treatment, the most powerful trigger of the HS response, should be effective in re-establishing SIRT1-HSF1-HSP axis in atherosclerotic mice.
Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, heat treatment completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of triacylglycerols, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose, and insulin resistance while rising HDL-cholesterol levels. Heat treatment also decreased body weight gain, visceral fat, cellular infiltration, and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance indices. Remarkably, heat-treated mice stopped dying after the third heat treatment session, suggesting a curative effect.