Systemic adiponectin malfunction as a risk factor for cardiovascular disease

Abstract

Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30 kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory and anti-ischemic (resulting in cardioprotective) effects have also been discovered. Since its 1995 discovery, Ad has garnered considerable attention for its role in diabetic and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, and insulin resistance. In this review, we elaborate currently known information about Ad malfunction and deficiency pertaining to cardiovascular disease risk (including atherosclerosis, endothelial dysfunction, and cardiac injury), as well as review evidence supporting Ad resistance as a novel risk factor for cardiovascular injury, providing insight about the future of Ad research and the protein's potential therapeutic benefits.

FIG. 1.

Structure of Ad (human). Full-length Ad requires post-translational modifications (e.g., hydroxylation and glycosylation) for activity. Ad molecules are secreted from adipocytes as trimers (∼90 kDa; the basic unit), LMW hexamers (∼180 kDa), and HMW isoforms (12–18-mers; >400 kDa). AA, amino acid (length); Ad, adiponectin; C, carboxy-terminus; HMW, high molecular weight; LMW, low molecular weight; N, amino-terminus. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Ad and the Ad receptor. Ad interacts with the extracellular C-terminus region of the Ad receptor, which spans the membrane in seven domains, with its N-terminus intracellular, interacting with APPL1. T-cadherin is postulated to be a receptor for multimeric HMW Ad isoforms, with yet unknown biologic function. AdipoR1/R2, Ad receptor 1/2; APPL1, adapter protein. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

AMP Kinase-dependent metabolic functions of Ad. Ad interacts with the extracellular C-terminus region of the Ad receptor, which spans the membrane in seven domains, with its N-terminus intracellular, and causes activation of AMP kinase. Of the four identified central biological functions for Ad, its metabolic regulatory function and vascular protective function are dependent upon the AMP kinase signaling axis. ACC, acetyl co-A carboxylase; AMPK, AMP-activated protein kinase; CPT1, carnitine palmotyltransferase 1; G6Pase, glucose-6-phosphatase; GF, growth factors; PEPCK, phosphoenolpyruvate carboxykinase. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

AMP Kinase-independent metabolic and antioxidant functions of Ad. Recent experimental results from many investigators, including our own, demonstrated that several AMPK-independent pathways exist that mediate Ad's anti-inflammatory, vascular protective, and cardioprotective/anti-ischemic functions. The interaction of Ad with calreticulin/CD91 complex has been demonstrated to lead to both anti-inflammatory and vascular protective effects in an AMPK-independent manor. A still un-identified mechanism is responsible for Ad's antioxidative/cardioprotective effects (likely via adenylate 29 cyclase/cAMP/PKA). cAMP, cyclic AMP; COX-2, cyclooxygenase 2; CRT, calreticulin; iNOS, inducible nitric oxide synthase; NOX2, NADPH oxidase 2/gp91phox; PKA, protein kinase A; TNFα, tumor necrosis factor alpha. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 5.

Ad signaling in endothelial cells. Ad signaling transduction pathways suppress endothelial cell activation elicited by high glucose levels and agonists such as TNF, and suppresses inflammatory responses (IKKβ and NFκβ activation). Ad enhances NO generation via AMP kinase cascade activation, and the cAMP-PKA pathway has been shown to mediate Ad's antioxidative and anti-inflammatory protective effects. CAMs, cell adhesion molecules; eNOS, endothelial nitric oxide synthase; Hsp90, heat shock protein 90; IKKβ, Iκβ kinase; NFκβ, nuclear factor κβ; NO, nitric oxide; ROS, reactive oxygen species. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 6.

Ad signaling in cardiomyocytes. Ad isoforms have been shown to exert multiple actions, such as activation of AMP kinases, CRT/CD91 activation with COX-2 involvement, suppression of TNF signaling via a COX-2-prostaglandin E2-linked cascade (26a), and reduction of oxidative and nitrative stress after MI/R injury that is associated with suppression of iNOS induction. CD91, CRT adapter protein; MI/R, myocardial ischemia-reperfusion. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).