Resistin: functional roles and therapeutic considerations for cardiovascular disease

Abstract

Resistin, originally described as an adipocyte-specific hormone, has been suggested to be an important link between obesity, insulin resistance and diabetes. Although its expression was initially defined in adipocytes, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages, spleen and bone marrow cells. Increasing evidence indicates that resistin plays important regulatory roles apart from its role in insulin resistance and diabetes in a variety of biological processes: atherosclerosis and cardiovascular disease (CVD), non-alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and chronic kidney disease. As CVD accounts for a significant amount of morbidity and mortality in patients with diabetes and without diabetes, it is important to understand the role that adipokines such as resistin play in the cardiovascular system. Evidence suggests that resistin is involved in pathological processes leading to CVD including inflammation, endothelial dysfunction, thrombosis, angiogenesis and smooth muscle cell dysfunction. The modes of action and signalling pathways whereby resistin interacts with its target cells are beginning to be understood. In this review, the current knowledge about the functions and pathophysiological implications of resistin in CVD development is summarized; clinical translations, therapeutic considerations and future directions in the field of resistin research are discussed.

Linked articles: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.

Figure 1

A schematic representation of potential mechanisms by which resistin may mediate cardiovascular dysfunction. Resistin possibly binds to the membrane bound TLR4 receptor, which then activates the intracellular signalling pathway. Resistin can activate the translocation of NFκB into the nucleus, which in turn, activates the transcription of pro-inflammatory cytokine genes, contributing to the proliferation of VSMCs and endothelial dysfunction. Activation of NFκB can also be mediated by the resistin-induced activation of PI3K/AKT pathway. Resistin can also stimulate the production of pro-inflammatory cytokines through MAPK p38 and JNK. Resistin can cause oxidative stress, which is another factor for MAPK activation and eNOS inhibition. Resistin increases the production of superoxide anions, which inhibit eNOS gene expression and reduce bioavailability of NO. VSMC proliferation and endothelial dysfunction including impaired vasorelaxation, enhanced thrombosis, hyper-permeability, angiogenesis and increased cell adhesion collectively contribute to the formation of atherosclerosis. Solid red arrows indicates activation, while broken blue lines indicate inhibition. eNOS, endothelial nitric oxide synthase; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa B; NO, nitric oxide; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; TLR4, toll-like receptor 4; VSMC, vascular smooth muscle cell.