Protective vascular and myocardial effects of adiponectin

Abstract

Adiponectin is an abundant plasma protein secreted from adipocytes that elicits protective effects in the vasculature and myocardium. In obesity and insulin-resistant states, adiponectin levels are reduced and loss of its protective effects might contribute to the excess cardiovascular risk observed in these conditions. Adiponectin ameliorates the progression of macrovascular disease in rodent models, consistent with its correlation with improved vascular outcomes in epidemiological studies. The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action. In endothelial cells, adiponectin enhances production of nitric oxide, suppresses production of reactive oxygen species, and protects cells from inflammation that results from exposure to high glucose levels or tumor necrosis factor, through activation of AMP-activated protein kinase and cyclic AMP-dependent protein kinase (also known as protein kinase A) signaling cascades. In the myocardium, adiponectin-mediated protection from ischemia-reperfusion injury is linked to cyclo-oxygenase-2-mediated suppression of tumor necrosis factor signaling, inhibition of apoptosis by AMP-activated protein kinase, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress. In this Review, we provide an update of studies of the signaling effects of adiponectin in endothelial cells and cardiomyocytes.

Figure 1

Structure of adiponectin. Full-length adiponectin requires post-translational modifications for activity (e.g. hydroxylation and glycosylation). Adiponectin molecules are secreted from adipocytes as trimers (∼90 kDa; the basic unit), low molecular weight hexamers (∼180 kDa) and high molecular weight isoforms (12-18-mers; >400 kDa). Abbreviations: aa, amino acids; C, carboxy terminal; HMW, high molecular weight; LMW, low molecular weight; N, amino terminal.

Figure 2

Adiponectin signal-transduction pathways suppress endothelial cell activation elicited by high glucose levels and agonists such as TNF. Adiponectin isoforms signal via specific cell-surface receptors to elicit anti-inflammatory responses (suppression of IKKβ and NFκB activation) coupled with enhanced NO generation and suppressed production of ROS. Activation of the AMP kinase cascade has been linked to adiponectin’s enhancement of NO generation, and the cAMP-PKA pathway has been shown to mediate adiponectin’s antioxidative and anti-inflammatory protective effects. Abbreviations: ADIPOR1, adiponectin receptor protein 1; ADIPOR2, adiponectin receptor protein 2; AMP kinase, AMP-activated protein kinase; cAMP, cyclic AMP; CAMs, cell adhesion molecules; eNOS, endothelial nitric oxide synthase; Hsp90, heat shock protein 90; IKKβ, IκB kinase; NFκB, nuclear factor κB; NO, nitric oxide; PI3K, phosphatidylinositol 3 kinase; PKA, protein kinase A; ROS, reactive oxygen species; TNF, tumor necrosis factor.

Figure 3

Adiponectin signaling in cardiomyocytes. Adiponectin isoforms have been shown to exert multiple actions, such as activation of AMP kinases, suppression of TNF signaling via a COX-2-prostaglandin E₂-linked cascade, and reduction of oxidative and nitrative stress after MIR injury that is associated with suppression of iNOS induction. Abbreviations: ADIPOR1, adiponectin receptor protein 1; ADIPOR2, adiponectin receptor protein 2; AMP kinase, AMP-activated protein kinase; COX-2, cyclo-oxygenase 2; iNOS, inducible nitric oxide synthase; MIR, myocardial ischemia-reperfusion; NO, nitric oxide; SK1, sphingosine kinase 1; TNF, tumor necrosis factor.