COMMENTARIES

Could Adiponectin Reduce Atherosclerotic Plaque Sizes Via Paracirne Pathway in Blood Vessels?

Chang-Jiang Li, Hui-Wen Sun, and Mei Zhang,
The Key Laboratory of Cardiovascular Remodeling and Function Research,
Chinese Ministry of Education and Chinese Ministry of Public Health,
Shandong University Qilu Hospital,
Jinan, Shandong, 250012,
P.R. China
Please address correspondence to:
Mei Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research
Chinese Ministry of Education and Chinese Ministry of Public Health
Shandong University Qilu Hospital
No. 107#, Wenhua Xi Road
Jinan, Shandong, 250012, P.R. China
Tel.: +86 531-8616-9356
Fax: +86 531-8616-9356
E-mail: daixh@vip.sina.com

Traditionally, adipose has been considered a simple energy storage tissue, but mounting evidence suggests that it can produce and secrete many bioactive substances, collectively referred to as adipocytokines. One of these, adiponectin, has significant roles in regulating the metabolism of glucose and fatty acids and in protecting against atherosclerosis. Adiponectin is a collagen-like protein whose gene is located on human chromosome 3q27 and is named as apM 1 gene. The full-length of apM 1 gene is 17 kbp, which includes 3 exons and 2 introns. The full-length of apM 1 mRNA is 4,517 bp.

Anti-atherosclerotic Effects of Adiponectin

Secreted by adipocytes, adiponectin plays significant roles in regulating the metabolism of glucose and fatty acids and in preventing atherosclerosis. Low plasma adiponectin levels are associated with insulin resistance and risk of type 2 diabetes. Adiponectin reduces the size of atherosclerotic lesions and inhibits neointimal thickening and proliferation of vascular smooth muscle cells in injured arteries and suppresses the expression of vascular adhesion molecules. Okamoto et al. reported that injection of adenovirus expressing the full-length adiponectin cDNA (Ad-APN) into the tail vein of apolipoprotein E-deficient mice inhibited lesion formation by 30% [1]. In another study, low plasma adiponectin levels were found to be associated with progression of subclinical coronary atherosclerosis in people with type 1 diabetes and in non-diabetes subjects independently of other cardiovascular risk factors [2].

    Although the mechanism for the protective contribution against atherosclerosis of adiponectin is unclear at present, the cytokine could inhibit TNF-α-induced expression of adhesive molecules by blocking nuclear factor-?B, and it could inhibit proliferation of smooth muscle cells induced by growth factors by inhibiting mitogen activated protein pathways [3]. Adiponectin has been shown to reduce atherosclerosis through attenuating endothelial inflammatory response and macrophage-to-foam cell transformation [1]. Meanwhile,adiponectin suppresses the expression of NF-?B-inducible genes, including VCAM-1, in endothelial cells and class A scavenger receptor expression in monocyte-derived macrophages [3,4]. In a recent study, we investigated the expression of VCAM-1 and ICAM-1 in abdominal aortas of atherosclerotic rabbits treated with Ad-APN via intima and adventitia [5]. Ad-APN treatment inhibited the expression of VCAM-1 and ICAM-1 in vivo but did not significantly affect the synthesis of type I and III collagen. The findings suggest that adiponectin improves atherosclerosis in part through inhibiting the expression of VCAM-1 and ICAM-1 in the vascular wall but not through regulating type I and III collagen synthesis. This is an interesting phenomenon and sheds a light on the adipose tissue surrounding blood vessels. Could adiponectin play an anti-atherosclerosis role through paracrine pathway?

Adiponectin and Adventitia

The vascular adventitia is defined as the outermost connective tissue of vessels. Recently, the adventitia was increasingly considered a highly active segment of vascular tissue that contributes to a variety of disease pathologies, including atherosclerosis and restenosis [6,7]. It has been found to secrete many vasoactive substances in a paracrine way to regulate the relaxation and construction of blood vessels and to influence the structure of blood vessels. Nitrogen oxide (NO) is an important vasoactive substance that could be synthesized by adventitial myofibroblast cells [8]. Zhang et al. reported that adventitia was a source of inducible nitric oxide synthase (NOS) in the rat aorta [9]. The mRNA expression and protein production of iNOS of adventitia increased following cytokine stimulation, thus increasing NO production. As reported in other studies, NO inhibits the proliferation of vascular smooth muscle cells to improve vascular stenosis [10]. As shown in several studies, adiponectin has been found to increase the NO production in vascular endothelial cells [11,12]. From our viewpoint, adiponectin could stimulate iNOS in adventitia and then NO production was elevated. Adiponectin plays anti-atherosclerosis role by the effects of NO such as inhibiting the proliferation of vascular smooth muscle cells. But more works are needed to confirm this hypothesis.

Effects of Therapeutic Interventions

Therefore, adiponectin is a target deserving more researches on decreasing morbidity and mortality of atherosclerotic disease in the future. How to increase plasma adiponectin levels? Several studies report that prolonged weight loss and lifestyle changes increase adiponectin levels [13,14]. Thiazolidinediones, PPARγ agonist, improves insulin sensitivity, and increases adiponectin levels. A recent study investigated the effects of a new beta-blocker in hypertensive patients [15]. Results showed that nebivolol, in contrast to metoprolol, improved oxidative stress and insulin sensitivity, decreased plasma soluble P-selectin and increased adiponectin levels. More studies are needed to investigate the mechanism of increased adiponectin levels. Recombinant adiponectin may play an important role in the field of prevention and treatment of atherosclerosis in the future.

References

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  2.    Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation 2005;111(6):747-53.
  3.    Lappas M, Yee K, Permezel M, et al. Sulfasalazine and BAY 11-7082 interfere with the nuclear factor-kappa B and I kappa B kinase pathway to regulate the release of proinflammatory cytokines from human adipose tissue and skeletal muscle in vitro. Endocrinology 2005;146(3):1491-97.
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  5.    Li CJ, Sun HW, Zhu FL, et al. Local adiponectin treatment reduces atherosclerotic plaque size in rabbits. J Endocrinol 2007;193(1):137-45.
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  10.    Scott-Burden T, Vanhoutte PM. Regulation of smooth muscle cell growth by endothelium-derived factors. Tex Heart Inst J 1994;21(1):91-97.
  11.    Chen H, Montagnani M, Funahashi T, et al. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 2003;278(45):45021-26.
  12.    Hattori Y, Suzuki M, Hattori S, et al. Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia 2003;46(11):1543-49.
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