Turning up the heat: heat shock proteins, hypertension and cardiovascular risk.

Abstract

From bacteria to man, cells respond to stress with the rapid transcription and translation of a highly conserved set of molecules, termed heat shock proteins (HSPs). HSPs are an important component of the homeostatic response to cellular stress, chaperoning and protecting protein-containing structures, particularly as they traffic across cell membranes [1]. This creates tolerance to insults such as ischaemia, hypoxia and oxidative stress. In addition, HSPs exert cytokine-like activity, inducing tumour necrosis factor-α, interleukin-12 and matrix metalloproteinase production in macrophages and expression of adhesion molecules on endothelial cells [2]. While predominantly intracellular, HSPs are also selectively released from cells where they elicit a variety of immunoregulatory functions through cell surface receptors [3]. Reactivity to HSPs has been implicated in autoimmunity, allograft rejection and ageing [1]. However, the greatest attention has focused on the role of HSPs in the pathogenesis of atherosclerotic disease. HSPs appear to have an important role in maintaining vascular homeostasis [4]. Injury and inflammation are clearly integral to the development of atherosclerosis. Therefore, it comes as little surprise that macrophages, endothelial and smooth muscle cells in atherosclerotic lesions express elevated levels of HSPs, correlating with the severity of disease [5]. Expression of HSPs are increased in early atherosclerotic lesions, particularly in local dendritic cells [6]. In addition, HSP expression in arterial cells can be induced by arterial injury [2], oxidized low-density lipoprotein [7] and acute hypertension [4]. Elevated levels of antibodies directed against HSP have been demonstrated in patients with carotid atherosclerosis [8], coronary heart disease (CHD) [9] and peripheral vascular disease [10]. In this issue of the journal, Pockley et al. [11] suggest another possible link between HSP and cardiovascular disease. Following on from previous studies in borderline hypertension [12], they demonstrate that subjects with established hypertension have increased levels of antibodies to HSP 65 and HSP 70. The physiological significance of these findings remains to be established. It is known that vessels subjected to mechanical and shear stress liberate immunogenic heat shock proteins [7]. It is therefore possible that antibodies become elevated in response to the extracellular release of HSPs and are therefore a marker of previous vascular stress. To support this notion, increased levels of circulating HSPs have been demonstrated in patients with CHD, again correlating with the severity of atherosclerotic disease [5]. Previous studies by Pockley et al. also showed increased HSP in borderline hypertension [12]. However, patients with established hypertension did not have increased HSP levels [11]. Certainly, HSPs are released into the circulation following acute hypertension [4]. However, chronic hypertension may have a different effect. Similar to patients with established hypertension, spontaneously hypertensive rats do not show elevated HSP expression, even though their basal blood pressures are sufficient to induce the response in normotensive Wistar–Kyoto rats [4]. One explanation may be that the heat shock response to vascular stress attenuates with prolonged exposure, creating the ‘normal’ HSP levels in patients with established hypertension with a resetting of the threshold for HSP induction. The presence of persistently elevated antibodies therefore represents a marker of previous HSP elevations such as that seen in untreated patients with borderline hypertension [12]. Other studies have suggested that the coronary risk conferred by HSP antibodies is independent of blood pressure levels or other concurrent diseases [9]. It is therefore possible that an elevation of HSP antibodies may also represent a shared marker in patients with increased cardiovascular risk. This risk may be genetic, with a close association demonstrated between HSP antibodies and inheritable polymorphisms in interleukin-6 [13]. In addition, microbial infection, implicated in the pathogenesis of both hypertension and atherosclerotic disease, may have a role in initiating and maintaining production of self-reacting HSP antibodies (due to the high HSP sequence homology across most species) [5]. Recent evidence also indicates that auto-reactive HSP antibodies are not simply markers of previous vascular stress, but may also contribute directly to the development of vascular disease. For example, immunization with recombinant HSP can induce atherosclerotic lesions [14]. Antibodies to HSPs may directly damage HSP-expressing cells through antibody-dependent cytotoxicity [5], and complement-activating HSP antibodies have recently been reported to be associated with CHD and were found to be predictive of future cardiovascular events [15]. It is therefore possible that induction of auto-reactive antibodies (through extracellular release of HSP, infection, an inherited trait or otherwise) directly contributes to cardiovascular risk and hypertension and supports the emerging concept of atherosclerosis as an ‘autoimmune’ vascular disease.