This article discusses the role of heat shock proteins (Hsps) and their receptors as anti-inflammation targets. Hsps are highly conserved proteins that protect cells against noxious or deleterious stimulus. Intracellular Hsps function as molecular chaperones governing protein assembly, folding, or transport and as anti-apoptotic regulators of cell signalling pathways leading to cell death. In addition, intracellular Hsps have recently been shown to have an anti-inflammatory role in various inflammatory conditions such as infection, ischemia/reperfusion injury, and cardiovascular diseases. However, the heat shock response and the induction of Hsps have paradoxical effects against cell injury. Hsp induction before a pro-inflammatory stimulus is clearly beneficial but Hsp induction after a pro-inflammatory stimulus is cytotoxic. These paradoxical and contradictory effects may result from the different functions of intracellular versus extracellular Hsps. Extracellular Hsps released from cells with compromised integrity may function as danger signals activating innate immunity by interacting with their receptors. Therefore, modulating the levels of intracellular Hsps or the activities of Hsp receptors will be potential drug targets in inflammation.

After heat shock or other metabolic stress, heat shock proteins (Hsps) are expressed at high levels in all tissues and cells. The highly inducible 70 kDa heat shock protein (Hsp70) is associated with improved post-ischemic myocardial contractile recovery. Similarly, the small 27 kDa heat shock protein (Hsp27), that is abundant in muscle, is also linked with improved myocardial function after ischemic injury. Various Hsps have pro-survival functions that include chaperone, anti-apoptotic and/or anti-inflammatory activity. In this review we will summarize our understanding of myocardial protection and present evidence for protection having time dependent aspects that appear to be stimulus dependent.

Heat shock proteins (HSPs) are critical for cell survival and have several mechanisms of action. HSPs regulate protein folding, suppress apoptosis, and regulate anti-oxidative activity. In addition, HSPs are involved in the regulation of the pro-inflammatory transcription factor nuclear factor (NF)-kappaB. When angiotensin (Ang) II is infused into rats, there is a significant increase in systolic blood pressure, and NF-kappaB is activated in the heart. If rats are heat shocked to induce the heat shock response and HSPs before Ang II infusion, there is a significant suppression of both the Ang II-induced increase in blood pressure and NF-kappaB activation in the heart. Although the role of specific HSPs in the regulation of NF-kappaB is unclear, several HSPs, including Hsp27 and Hsp70, are thought to be involved in the regulation of Ang II-induced NF-kappaB. The role of Hsp27 and Hsp70 in NF-kappaB activation is reviewed here, along with evidence suggesting that HSPs regulate Ang II-induced blood pressure through the regulation of NF-kappaB.

Hsp27 may regulate the phosphorylation of the p65 subunit of NF-kappaB in the Ang II-induced signaling pathway of NF-kappaB in A10 cells. The proinflammatory effects of Ang II on NF-kappaB in vascular smooth muscle cells may be through a non-canonical pathway and be dependent on p65 phosphorylation.