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Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.

ABSTRACT: Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB(2) was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median: 4.0 versus 3.02 ng/mL; P=0.013). Twelve patients (14%) with metabolic syndrome, but none without metabolic syndrome, had sTxB(2) levels consistent with inadequate inhibition of COX (sTxB(2) ?13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB(2) (P=0.006). Higher levels of sTxB(2) associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB(2) levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydro thromboxane B(2) did not correlate with sTxB(2), suggesting that the former should not be used to quantitate aspirin's pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.

SUBMITTER: Smith JP

PROVIDER: S-EPMC3418792 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.

Smith James P JP Haddad Elias V EV Taylor Mary B MB Oram Denise D Blakemore Dana D Chen Qingxia Q Boutaud Olivier O Oates John A JA

Hypertension (Dallas, Tex. : 1979) 20120206 3

Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicat ...[more]

PMID: 22311905

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Project description:BackgroundMetabolic syndrome-associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA.MethodsAnalysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system.ResultsHumans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal antiinflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA.ConclusionsOur findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential.FundingThis work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to MW, R01AR079620 to SD, and P01AG066603 to XC.

Dataset Information

Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.

Publications

Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.

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