Vasoactive Factors and Inflammatory Mediators Produced in Adipose Tissue
5. MOLECULAR LINKS UNDERLYING THE ADIPOSITY–
INFLAMMATION–IMMUNITY CLUSTER
The body of knowledge of the pathophysiological effects of adipokines on vaso- activity and inflammation has been gathered from different types of studies, including epidemiological observations, animal model experiments, in vitro approaches, and microarray application. The consistent interrelationship between several adipokines with known effects on inflammation, atherosclerosis, and insulin resistance provides support for the crucial role of adipose tissue in the regulation of obesity-linked CV derangements. Although the existence of inflammatory events is well-known to exert a
relevant role in CHD etiology, the exact mechanisms underlying this relationship have not been completely disentangled. For instance, it has not been established whether adipokines simply act as markers of the acute phase reaction or are directly involved as causative factors. Most probably both statements are applicable, with adipokines oper- ating as markers and simultaneously exhibiting a causal implication.
The molecular mechanisms linking the adiposity–inflammation–immunity cluster are complex and their understanding is in continous evolution. The triad of obesity–insulin resistance–CVD is interwoven in a setting of inflammation, endothelial dysfunction, and atherosclerosis. Obesity is characterized by a low-grade systemic inflammation and a hypercoagulable state contributing to atherosclerosis. Endothelial dysfunction repre- sents an early pivotal event in the pathogenesis of atherosclerosis, with a manifest imbalance between endothelium-dependent vasodilation and vasoconstriction taking place in a prothrombotic environment. The endothelial vasodilatory capacity is main- tained by NO, which opposes the vasoconstrictor influences of angiotensin II and endothelin-1 (72). The maintenance of the endothelium as a smooth nonthrombotic bar- rier is further acomplished by prostacyclins and the inhibitory effect on leukocyte and platelet activation and aggregation (16). Adhesion molecules such as the vascular (VCAM-1) and intercellular (ICAM-1) ones are known to be increased in response to inflammatory insults. The elevated expression of P- and E-selectins contributes—
together with MCP-1 and integrins—to increase leukocyte recruitment, transmigration, and subsequent adherence to the intima media (73). Phagocytosis of oxidized LDL par- ticles by monocytes leads to foam cell formation and the development of fatty streaks and plaques together with VSMC proliferation (16). In addition, the inflammatory IPB kinase-G/NFPB pathway has been demostrated to also mediate insulin resistance (74).
Adipokines are known to impinge on all these pathways, which provide the complex molecular links underlying obesity and the development of CV alterations (Fig. 4).
6. CONCLUSIONS
In conclusion, the notion of adipose tissue as a passive bystander in energy homeo- stasis has been surpassed. This almost ubiquitously distributed, extraordinarily active endocrine organ has emerged as a dynamic and pleiotropic tissue. The multifunctional nature of adipose tissue is based on the ability of its cellular constituents to secrete a large number of hormones, growth factors, enzymes, cytokines, complement factors, and matrix proteins, collectively termed adipokines or adipocytokines, at the same time as they express receptors for most of these factors. Only recently has attention been devoted to the vasoactive factors produced by adipose tissue. The extensive crosstalk at both a local and systemic level in response to neuroendocrine stimuli as well as metabolic changes warrants a key role in processes well beyond body weight con- trol and insulin resistance, such as inflammation, coagulation, fibrinolysis, and athero- sclerosis.
The exact contribution of the complex network of bioactive mediators on vasoactiv- ity and inflammation remains to be fully determined. Furthermore, it will be interest- ing to gain more insight into the mechanisms involved in the activation and integration of the diverse signaling pathways. It will be also worthwhile to focus on how the known vasoactive factors are related to the more recently discovered hormones,
adipokines, receptors, channels, and peptides such as obestatin, adrenomedullin, hypoxia- sensitive molecules, aquaporins, and caspases. In addition, major advances in disent- angling the molecular mechanisms underlying inflammation and atherogenesis are to be expected. Undoubtedly, given adipose tissue’s versatile and ever-expanding list of activities, additional and unexpected vasoactive peptides are sure to emerge. The intense studies under way on many different frontiers of cardiovascular investigation will add more information to the already large body of knowledge representing a fertile and exciting research field.
ACKNOWLEDGMENTS
This work was supported by grant 20/2005 from the Department of Health of the Gobierno de Navarra, and the Instituto de Salud Carlos III-FIS of Spain.
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