Association of serum antibodies to heat-shock protein 65 with coronary calcification levels: suggestion of pathogen-triggered autoimmunity in early atherosclerosis.

BACKGROUND: Previous studies demonstrated an association between antibodies to mycobacterial heat-shock protein 65 (mHSP65) and carotid artery thickening. We examined whether mHSP65 antibodies are associated with levels of coronary calcification that appear to reflect preclinical coronary artery disease (CAD). METHODS AND RESULTS: Serum specimens from 201 healthy asymptomatic subjects (52% male; mean age, 56.6 years) undergoing electron-beam computed tomographic imaging were used to measure levels of mHSP65 and human HSP60 antibodies and antibodies to several infectious pathogens. We found that 84% of the study subjects had anti-mHSP65 IgG antibodies. Mean titers of mHSP65 antibodies were higher (1:394 versus 1:267, P=0.012) in individuals with than in those without elevated levels of coronary calcium (calcium score > or =150). Increasing titers of mHSP65 antibodies were significantly associated, in a dose-response manner, with elevated levels of coronary calcification. Individuals with the highest titers of mHSP65 antibodies (> or =1:800) had an adjusted odds ratio (OR) of 14.3 for having elevated coronary calcium (P=0.004). Association of mHSP65 antibodies with elevated coronary calcification levels was independent of CAD risk factors after multivariate adjustment (P=0.037). Interestingly, mHSP65 antibody titers were correlated with Helicobacter pylori infection (P=0.004), which maintained significance after adjustment for CAD risk factors and seropositivities to other pathogens (adjusted OR, 3.1; 95% CI, 1.4 to 6.6). No association was found between antibodies to human HSP60 and levels of coronary calcification. CONCLUSIONS: Antibodies to mHSP65 are associated with elevated levels of coronary calcification and correlated with H pylori infection, suggesting that pathogen-triggered autoimmunity plays a role in early atherosclerosis.

Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice.

OBJECTIVES: We examined whether selective cyclooxygenase-2 (COX-2) inhibition in apolipoprotein-E (apoE) deficient mice reduces cytomegalovirus (CMV) replication, and determined whether COX-2 anti-inflammatory activity leads to decreased atherosclerosis. BACKGROUND: Evidence suggests that CMV infection contributes to atherosclerosis and that this occurs in part through inflammatory mechanisms. Cyclooxygenase-2 inhibitors are potent anti-inflammatory agents. They also inhibit CMV replication in vitro. METHODS: The apoE deficient mice were either treated or not treated with a selective COX-2 inhibitor, and either infected or not infected with CMV. Viral deoxyribonucleic acid load in salivary glands was determined by quantitative polymerase chain reaction. Atherosclerotic lesion analysis was performed by standard methods. RESULTS: In vivo COX-2 inhibition, unexpectedly increased viral load: in the CMV-infected animals viral load was 2.58 +/- 1.0 in the nontreated group, 4.74 +/- 1.38 in the group treated with 12 mg/kg/day MF-tricyclic, and 6.51 +/- 1.64 in the group treated with 24 mg/kg/day MF-tricyclic (p trend = 0.050). This increased viral load was paralleled by increased anti-CMV antibody titers. Most surprisingly, COX-2 inhibition significantly increased early atherosclerotic lesion area, independent of viral infection. CONCLUSIONS: Our study demonstrates that selective inhibition of COX-2 in vivo increases viral load. The finding that inhibition of COX-2 increases atherosclerosis development in apoE deficient mice suggests, unexpectedly, that this enzyme exerts antiatherosclerosis activity, at least in this model.

Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease.

OBJECTIVE: Previous studies suggest that heat shock protein (HSP) 60 has a contributory role in atherosclerosis development. We examined whether circulating HSP70 protein and anti-HSP70 antibodies are associated with coronary artery disease (CAD). METHODS AND RESULTS: Blood samples from 421 patients (62% men, mean age 57 years) evaluated for CAD by coronary angiography were tested. Serum HSP70 was detectable in 67% of study subjects with levels ranging from 0.2 to 27.1 ng/mL (mean, 1.08; median, 0.5). HSP70 levels were higher in non-CAD patients than CAD patients (median, 0.72 versus 0.34; P=0.0006). Individuals with HSP70 levels above the median (0.5 ng/mL) had half the risk of CAD than individuals with levels below the median (adjusted odds ratio, 0.52; 95% confidence limit, 0.32 to 0.86). The association of high HSP70 levels with low CAD risk was independent of traditional CAD risk factors (P=0.011). Disease severity (number of diseased vessels) was also inversely associated with HSP70 protein levels (P=0.010). The adjusted odds ratio of having multivessel disease for patients with high HSP70 protein levels was 0.54 (95% confidence limit, 0.36 to 0.81). In contrast, no association between anti-HSP70 IgG seropositivity and the prevalence of CAD was found (P=0.916). CONCLUSIONS: These data provide the first evidence that high levels of human HSP70 are associated with the low CAD risk, probably through its multiple protective effects on a cell's response to stress.