Genetic variations of HSPA1A, the heat shock protein levels, and risk of atherosclerosis.

HSPA1A is a serum and intracellular heat shock protein with antiapoptotic and antithrombotic properties. The present study examines the hypothesis that a decrease in the synthesis of this protein in relation to certain polymorphisms of the regulatory region of the HSPA1A gene can define a vascular disease risk phenotype. A randomly selected population was studied and stratified into groups according to the degree of vascular risk. After applying the Task Force Chart to 452 people, the subjects were divided into three groups: group 0 (no vascular risk factor or risk < 5%), n = 239; group 1 (moderate (10-20%) risk, with no clinical cardiovascular disease), n = 161; and group 2 (overt atherosclerosis), n = 52. Serum and intragranulocytic HSPA1A was quantified, and direct Sanger sequencing was performed in all subjects. An analysis was made of the association of two single nucleotide polymorphisms (db rs1008438 -110A/C and db rs1043618 +190 G/C) with circulating and intragranulocytic HSPA1A and the risk of atherosclerosis. The atherosclerotic subjects showed significantly lower circulating HSPA1A levels than the other groups, regardless of the genotype. The patients with CC genotype for both polymorphisms showed significantly lower intragranulocytic HSPA1A levels than the other genotypes. Serum HSPA1A concentrations could be proposed as a biomarker of cardiovascular disease. CC homozygosis for polymorphisms db rs1008438 and db rs1043618 is associated with a decrease in the intragranulocytic production of HSPA1A. Given the antiatherogenic functions of intracellular HSPA1A, the -110A and +190 G alleles could constitute potential genetic biomarkers of a less severe clinical phenotype for the risk of developing atherosclerosis.

Extracellular heat shock protein 70 (HSPA1A) and classical vascular risk factors in a general population.

Atherosclerosis is a chronic inflammatory and autoimmune disease. Candidate molecules/autoantigens include heat shock proteins (HSPs); Hsp70 (HSPA1A) is one of the best studied HSPs. Various studies have shown a correlation between extracellular Hsp70 (eHsp70) and anti-Hsp70/anti-Hsp60 antibody concentration and development of atherosclerosis. A random sample of 456 people aged 40-60 (218 males, 234 females) was studied to investigate the prevalence of traditional vascular risk factors and eHsp70 and anti-Hsp70/anti-Hsp60 antibodies levels, according to the risk of vascular disease. Task Force Chart was applied for classification. Subjects were divided into three groups: G0 (with no vascular risk factor or a risk lower than 5%), n = 239; G1 (moderated 10-20% risk, who do not have established disease) n = 161; and G2 (established atherosclerosis disease) n = 52. eHsp70 and anti-Hsp70 were significantly lower in the atherosclerosis group (group 2) with respect to the other groups. Disease-free people showed the highest anti-Hsp60 concentration compared with the other two groups. A correlation has not been demonstrated between the concentrations of circulating Hsp70 (HSPA1A), anti-Hsp70, and anti-Hsp60 and classical vascular risk factors and C-reactive protein. Low levels of eHsp70 and anti-Hsp70 antibodies should be considered as candidate FRV. Simultaneous decrease of eHsp70 and anti-Hsp70 antibodies would be explained by circulating immune complex formation, and both could be proposed as biomarkers for the progression of atherosclerotic disease. Levels of circulating anti-Hsp60 antibodies may constitute a marker of inflammation in atherosclerosis.

Reduction of heat shock protein antibody levels by statin therapy.

Atherosclerosis is a disease whose pathogenesis involves inflammatory and immunological mechanisms, including an autoimmune reaction against heat shock proteins (Hsps). The purpose of this study was to analyze whether the antiatherogenic effect of statin therapy was not limited to its lipid lowering effect, but also included anti-inflammatory and immunomodulatory effects, paying special attention to the measurement of circulating concentrations of anti-Hsp70 and anti-Hsp60 antibodies previously related to vascular disease. Two-hundred and seventy-five subjects aged 40-60 years, randomly selected in an epidemiological study on the incidence of vascular risk factors, were studied. Laboratory tests included a complete lipid profile after a 12-h fast and measurements of glucose, C-reactive-protein, anti-Hsp70 and anti-Hsp60 antibodies. Subjects with hypercholesterolemia had significantly higher concentrations of anti-Hsp70 antibodies as compared to subjects with normal cholesterol concentrations. Statin therapy was associated with 11.63 and 15.3% reductions in total and LDL-cholesterol (P = 0.005 and 0.017, respectively) as compared to untreated subjects, and with lower concentrations of circulating anti-Hsp70 (P = 0.016) antibodies. No differences were found in C-reactive-protein values. Since statin therapy not only reduces lipid profile, but also anti-Hsp70 and anti-Hsp60 antibody concentrations, without changing C-reactive-protein values, it is suggested that such an effect could not be accounted for by the anti-inflammatory properties of statins, but by their direct immunomodulatory properties through their effects on lymphocyte function.