Adiponectin in Atherosclerosis/Stroke

According to American Heart Association Statistics Committee and Stroke Statistics Subcommittee, approximately 700,000 people experience a new or recurrent stroke every year, and on an average, every 45 seconds someone in the United States suffers from a stroke.

Since adiponectin is associated with many cardiovascular risk factors, such as hypertension, type II diabetes, and an altered lipid profile, a link between adiponectin and stroke is expected. However, a meta-analysis of prospective cohort studies determined that plasma adiponectin levels are not a risk factor for the occurrence of the disease.

Yet, low plasma adiponectin levels have been observed poststroke, and in fact, decreased adiponectin levels predict increased risk of 5-year mortality after a first-ever ischemic stroke. Thus, the utility of plasma adiponectin levels in management of risk factors for stroke versus management of poststroke sequelae may differ, and this difference may be due to varying mechanisms of action elicited by adiponectin receptor signaling under differing conditions.

Adiponectin Protective Effects in Stroke

Despite unclear data on the correlations between serum adiponectin levels and stroke risk or recovery from stroke, there are several studies demonstrating adiponectin-mediated mechanistic effects that are protective against atherosclerosis as well as stroke pathogenesis. Circulating adiponectin inhibits monocyte adhesion to endothelial cells and inhibits macrophage transformation to foam cells by reducing oxidized LDL binding and uptake. This process is a crucial step in atherosclerosis as well as stroke pathogenesis.

Adiponectin also inhibits induction of vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1), which typically bind to leukocytes and initiate formation of atheroma following endothelial cell injury. The mechanism for reduction in adhesion molecules may be through activation of AdipoR2 which increases PPARα activity, since PPARα agonists can also reduce VCAM-1 and ICAM-1. Interestingly, a clinical trial with the PPARγ agonist rosiglitazone resulted in increased circulating levels of adiponectin and reduced circulating VCAM-1, indicating that PPARγ agonists may confer antiatherogenic properties through an increase in adiponectin.

Other studies show that elevated plasma adiponectin protects endothelial cells from hypercholesterolemia-induced vascular injury and suppresses the uptake of modified LDL into foam cells. In mouse models of atherosclerosis, adiponectin reduces the size of atherosclerotic lesions, whereas adiponectin knockout (APN-KO) mice exhibit excessive vascular remodeling in response to acute ischemic insult.

While APN-KO mice exhibit increases in breadth of cerebral infarct after ischemia-reperfusion, exogenous adiponectin reduces the infarct size in both APN-KO and wild type mice. Furthermore, adiponectin overexpression increases indices of positive behavioral outcomes as well as stimulates angiogenesis following ischemic injury. Therefore, adiponectin may regulate vascular remodeling, confer antiatherogenic properties within the vasculature, and afford protection against stroke and/or stroke severity.

Adiponectin Influences Nitric Oxide

Protective actions of adiponectin in stroke may also be due to stimulation of nitric oxide (NO) synthesis from endothelial cells, through AdipoR1 signaling. In case of acute stroke, intense vasospasm may occur over the first few weeks which can lead to increased morbidity and mortality. NO plays a significant protective role, since it causes vasodilation and increases blood flow. Adiponectin increases NO production through stimulation endothelial NO synthase (eNOS), and therefore, adiponectin may be neuroprotective following stroke. Usually, plasma NO production is increased in response to hypoxia/ischemia, but this response is absent in APN-KO mice.

Adiponectin treatment of bovine aortic endothelial cells increases NO production significantly, an effect mediated by phosphorylation of both Akt at Ser⁴⁷³ and eNOS at Ser¹¹⁷⁹ via phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Akt can also directly phosphorylate eNOS at Ser¹¹⁷, resulting in NO production and the regulation of vasomotor responses. Phosphorylation of Akt is activated by calmodulin-dependent protein kinase kinase (CaMKK), which then concomitantly phosphorylates eNOS in response to increased calcium in the cytoplasm.

The calcium-dependent activation of calmodulin stimulates CaMKK and the recruitment of calmodulin to eNOS, causing a “burst-like” release of NO. AMPK, which is also activated by adiponectin signaling, activates cardiac and endothelial cell eNOS by phosphorylation at Ser¹¹⁷⁷ (human sequence) in vitro. AMPK signaling is also required for vascular endothelial growth factor -stimulated endothelial cell NO production, migration, and differentiation in response to hypoxic conditions and increased oxidative stress in stroke, which also promotes angiogenesis in vivo. Therefore, adiponectin may play a significant protective role in stroke via influence on NO.