Adiponectin in atherosclerosis

Abstract

Adiponectin is a protein secreted from adipocytes, circulating at high levels in plasma (3 30μg/mL), and in overweight subjects it is down regulated. Adiponectin inhibits the development of atherosclerosis in experimental animal models but whether adiponectin is anti atherogenic in humans is not known. Furthermore, epidemiological studies on plasma adiponectin with regard to cardiovascular outcome are contradictory.

We therefore explored the relationship between plasma adiponectin, cardiovascular disease (CVD) and mortality in three separate studies in which the investigated subjects differed with respect to age, cardiovascular risk factors, and prevalence of CVD. Furthermore, we examined the relationship between plasma adiponectin and intima media thickness (IMT) in the common carotid artery (CCA), in the bifurcation of the carotid artery (Bif) at baseline and after 30 months progression. In addition, we analysed the associations of 1,214 single nucleotide polymorphisms (SNPs) in five loci ADIPOQ, ADIPOR1, ADIPOR2, CDH13, and ARL15 in relation to plasma adiponectin. The relationship between plasma adiponectin raising alleles and IMT measures was also investigated. We also explored the use of gene expression profiles, measured with Affymetrix® microarray technology, from carotid atherosclerotic plaques and from peripheral blood mononuclear cells for improving the prediction of ischaemic events, in addition to established risk factors.

In paper I, we demonstrated that low plasma adiponectin was associated with myocardial infarction in young individuals (<60 years) in an age and gender matched case control study of 244 survivors of first time myocardial infarction and corresponding controls. The relationship was independent of fasting glucose, high density lipoprotein cholesterol, hypertension and creatinine. In paper II, we showed that high plasma adiponectin was associated with cardiovascular and all cause mortality in 292 subjects who all had prevalent CVD and underwent carotid endarterectomy (CEA). No relation to ischaemic events (i.e. ischaemic stroke or myocardial infarction) was evident. In paper III, low plasma adiponectin was associated with cardiovascular and coronary events in a large cohort of 3,430 high–risk subjects with three or more cardiovascular risk factors, but without prevalent CVD. Plasma adiponectin was inversely associated with Bif IMT at baseline and progression of CCA IMT in men. We also showed that four SNPs in ADIPOQ were associated with plasma adiponectin and the finding was replicated in independent cohorts (n=6,576). The sum of plasma adiponectin raising alleles was inversely associated with Bif IMT in men but not in women. The association could, however, not be replicated in a smaller cohort of low risk subjects. In paper IV, we showed that adding gene expression profiles, from atherosclerotic plaques extirpated by CEA in 127 patients, to classical risk factors could improve prediction of ischaemic events.

In summary, prevalent CVD is an important divider for the relationships between plasma adiponectin and outcome measures; Low plasma adiponectin is associated with adverse outcome in subjects without prevalent CVD, whereas in subjects with prevalent CVD high plasma adiponectin is associated with mortality. Plasma adiponectin is inversely associated with early atherosclerosis and progression of atherosclerosis in men. Adiponectin raising alleles are inversely associated with early atherosclerosis in men, which supports a causal protective role of adiponectin in early atherosclerosis.

Additionally, gene expression profiling from atherosclerotic plaques improves prediction of ischaemic events in subjects with prevalent CVD.