Visceral adipose of obese mice inhibits endothelial inwardly rectifying K+ channels in a CD36-dependent fashion.

Obesity imposes deficits on adipose tissue and vascular endothelium, yet the role that distinct adipose depots play in mediating endothelial dysfunction in local arteries remains unresolved. We recently showed that obesity impairs endothelial Kir2.1 channels, mediators of nitric oxide production, in arteries of visceral adipose tissue (VAT), while Kir2.1 function in subcutaneous adipose tissue (SAT) endothelium remains intact. Therefore, we determined if VAT versus SAT from lean or diet-induced obese mice affected Kir2.1 channel function in vitro. We found that VAT from obese mice reduces Kir2.1 function without altering channel expression whereas AT from lean mice and SAT from obese mice had no effect on Kir2.1 function as compared to untreated control cells. As Kir2.1 is well known to be inhibited by fatty acid derivatives and obesity is strongly associated with elevated circulating fatty acids, we next tested the role of the fatty acid translocase CD36 in mediating VAT-induced Kir2.1 dysfunction. We found that the downregulation of CD36 restored Kir2.1 currents in endothelial cells exposed to VAT from obese mice. In addition, endothelial cells exposed to VAT from obese mice exhibited a significant increase in CD36-mediated fatty acid uptake. The importance of CD36 in obesity-induced endothelial dysfunction of VAT arteries was further supported in ex vivo pressure myography studies where CD36 ablation rescued the endothelium-dependent response to flow via restoring Kir2.1 and endothelial nitric oxide synthase function. These findings provide new insight into the role of VAT in mediating obesity-induced endothelial dysfunction and suggest a novel role for CD36 as a mediator of endothelial Kir2.1 impairment.NEW & NOTEWORTHY Our findings suggest a role for visceral adipose tissue (VAT) in the dysfunction of endothelial Kir2.1 in obesity. We further reveal a role for CD36 as a major contributor to VAT-mediated Kir2.1 and endothelial dysfunction, suggesting that CD36 offers a potential target for preventing the early development of obesity-associated cardiovascular disease.

Targeting Lipid-Ion Channel Interactions in Cardiovascular Disease.

General lipid-lowering strategies exhibit clinical benefit, however, adverse effects and low adherence of relevant pharmacotherapies warrants the investigation into distinct avenues for preventing dyslipidemia-induced cardiovascular disease. Ion channels play an important role in the maintenance of vascular tone, the impairment of which is a critical precursor to disease progression. Recent evidence suggests that the dysregulation of ion channel function in dyslipidemia is one of many contributors to the advancement of cardiovascular disease thus bringing to light a novel yet putative therapeutic avenue for preventing the progression of disease mechanisms. Increasing evidence suggests that lipid regulation of ion channels often occurs through direct binding of the lipid with the ion channel thereby creating a potential therapeutic target wherein preventing specific lipid-ion channel interactions, perhaps in combination with established lipid lowering therapies, may restore ion channel function and the proper control of vascular tone. Here we first detail specific examples of lipid-ion channel interactions that promote vascular dysfunction and highlight the benefits of preventing such interactions. We next discuss the putative therapeutic avenues, such as peptides, monoclonal antibodies, and aspects of nanomedicine that may be utilized to prevent pathological lipid-ion channel interactions. Finally, we discuss the experimental challenges with identifying lipid-ion channel interactions as well as the likely pitfalls with developing the aforementioned putative strategies.