Genetic variants of Y chromosome are associated with a protective lipid profile in black men.

OBJECTIVE: Gender and ethnicity modulate the phenotypic expression of cardiovascular risk factors. In particular, men are at higher risk of developing cardiovascular diseases compared to women, whereas black populations of African origin display reduced mortality from coronary heart disease (CHD) as compared to both whites and South Asians. Because the male-specific region (MSY) of the human Y chromosome is an obvious candidate for gender-related differences in the development of cardiovascular diseases, we aimed to identify genetic variants of MSY influencing cardiovascular risk profile in different ethnic groups. METHODS AND RESULTS: We genotyped 4 polymorphisms of MSY (HindIII+/-, rs768983 of TBL1Y, rs3212292 of USP9Y, and rs9341273 of UTY genes) in 579 men of different ethnic groups (blacks, South Asians, and whites) from UK and in 301 whites in Italy. We found that the TBL1Y(A) USP9Y(A) haplotype, present only in blacks in whom it represents the most frequent allelic combinations (AA: n=125; all other combinations: n=45), was associated with lower levels of triglycerides (P=0.025) and higher levels of HDL-cholesterol (P=0.005) as compared to the other haplotypes. CONCLUSIONS: The TBL1Y(A) USP9Y(A) haplotype of the Y chromosome, present only in black people of African origin, attributes a favorable lipoprotein pattern, likely to contribute to their reduced susceptibility to coronary heart disease.

Comparison of MMP-2 and MMP-9 secretion from T helper 0, 1 and 2 lymphocytes alone and in coculture with macrophages.

Metalloproteinases (MMPs) participate in extracellular matrix remodelling and regulatory signalling during chronic inflammatory states such as atherosclerosis formation. However, the sources and mediators of MMP upregulation need clarification. We investigated whether proinflammatory mouse T helper type 1 (Th1) lymphocytes are more active in MMP secretion than naïve Th0 or anti-inflammatory Th2 phenotypes, in the absence of specific antigenic stimulation, under baseline conditions and after contact with irradiated macrophages. We also compared the effect of Th0, Th1 or Th2 lymphocyte-conditioned medium and irradiated lymphocytes on MMP production from macrophages. Finally, we investigated whether CD40-CD40 ligand (CD40L) interactions were involved in T-cell-stimulated MMP secretion from macrophages. Under baseline conditions, MMP-2 messenger RNA (mRNA) and protein levels were greater in Th1 than Th0 or Th2 lymphocytes; MMP-9 mRNA, but not protein, was also upregulated. In the presence of irradiated macrophages MMP-2 and MMP-9 production from Th1 and Th2 was greater than from Th0 lymphocytes. Conditioned media from Th1 but not Th0 or Th2 cells increased MMP-9 secretion from macrophages. Irradiated Th1 lymphocytes stimulated both MMP-2 and MMP-9 secretion from macrophages more than irradiated Th2 or Th0 cells; this activation was independent of CD40-CD40L interaction. These findings demonstrate for the first time greater MMP secretion by Th1 than Th2 or Th0 lymphocytes and their greater ability to upregulate macrophage MMP secretion in the absence of specific antigenic stimulation. These mechanisms could promote matrix turnover in inflammatory states and, for example, promote atherosclerotic plaque rupture.

Destabilizing role of cathepsin S in murine atherosclerotic plaques.

OBJECTIVE: Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization. METHODS AND RESULTS: Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques. CONCLUSIONS: These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.

Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: model characterization and effects of pravastatin treatment.

BACKGROUND: These studies examined the early time course of plaque development and destabilization in the brachiocephalic artery of the apolipoprotein E-knockout mouse, the effects of pravastatin thereon, and the effects of pravastatin on established unstable plaques. METHODS AND RESULTS: Male apolipoprotein E-knockout mice were fed a high-fat, cholesterol-enriched diet from the age of 8 weeks. Animals were euthanized at 1-week intervals between 4 and 9 weeks of fat feeding. Acutely ruptured plaques were observed in the brachiocephalic arteries of 3% of animals up to and including 7 weeks of fat feeding but in 62% of animals after 8 weeks, which suggests that there is a sharp increase in the number of plaque ruptures at 8 weeks. These acute plaque ruptures then appear to heal and form buried fibrous caps; after 9 weeks of fat feeding, mice had 1.05+/-0.15 buried fibrous caps at a single site in the brachiocephalic artery. Pravastatin (40 mg/kg of body weight per day for 9 weeks; resultant plasma concentration 16+/-4 nmol/L) had no effect on plasma cholesterol concentration in fat-fed apolipoprotein E-knockout mice but reduced the number of buried fibrous caps by 43% (P<0.0001). In longer-term experiments, the delay of pravastatin treatment until unstable plaques had developed reduced the incidence of acute plaque rupture by 36% (P<0.0001). CONCLUSIONS: Plaque rupture occurs at high frequency in the brachiocephalic arteries of male apolipoprotein E-knockout mice after 8 weeks of fat feeding. Pravastatin treatment inhibits early plaque rupture and is also effective when begun after unstable plaques have developed.

Ethnic variation in levels of circulating IgG autoantibodies to oxidised low-density lipoprotein.

BACKGROUND: Oxidised low-density lipoprotein (Ox-LDL) plays a key role in atherosclerosis. Our aim was to determine whether serum autoantibodies against Ox-LDL (Ab Ox-LDL) differ by ethnic group. DESIGN AND METHODS: Soluble serum Ab Ox-LDL levels were measured in 250 white (113 females), 169 African origin (91 females) and 196 South Asian (92 females) individuals from the Wandsworth Heart and Stroke Study (WHSS) population. All were free from coronary heart disease (CHD), stroke, other cardiovascular disease, diabetes, drug therapy for hypertension or high lipids, hormone replacement therapy or oral contraceptive pill. RESULTS: There were no sex differences in levels of Ab Ox-LDL, but levels were higher in non-smokers (430U/L [95% CI 471-596]) than in smokers (384U/L [316-468]) (p<0.009). Age- and sex-adjusted levels of Ab Ox-LDL were higher in people of African origin and South Asians compared to whites. This difference was maintained in South Asian women following adjustment for multiple risk factors (82% [21-175]; p=0.004). Ab Ox-LDL levels were negatively associated with serum triglycerides and positively associated with sVCAM-1. CONCLUSIONS: Higher IgG Ab to Ox-LDL are associated with higher levels of sVCAM-1 and, are elevated in female South Asian individuals who have an increased risk of atherosclerosis compared to whites.