A Genetic Polymorphism in the Pannexin1 Gene Predisposes for The Development of Endothelial Dysfunction with Increasing BMI

Abstract

Endothelial dysfunction worsens when body mass index (BMI) increases. Pannexin1 (Panx1) ATP release channels regulate endothelial function and lipid homeostasis in mice. We investigated whether the Panx1-400A>C single nucleotide polymorphism (SNP), encoding for a gain-of-function channel, associates with endothelial dysfunction in non-obese and obese individuals. Myocardial blood flow (MBF) was measured by 13N-ammonia positron emission/computed tomography at rest, during cold pressor test (CPT) or dipyridamole-induced hyperemia. Myocardial flow reserve (MFR) and endothelial function were compared in 43 non-obese (BMI < 30 kg/m2) vs. 29 obese (BMI ≥ 30 kg/m2) participants and genotyping for the Panx1-400A>C SNP was performed. Groups comprised subjects homozygous for the C allele (n = 40) vs. subjects with at least one A allele (n = 32). MBF (during CPT or hyperemia), MFR and endothelial function correlated negatively with BMI in the full cohort. BMI correlated negatively with MFR and endothelial function in non-obese Panx1-400C subjects, but not in Panx1-400A individuals nor in obese groups. BMI correlated positively with serum triglycerides, insulin or HOMA. MFR correlated negatively with these factors in non-obese Panx1-400C but not in Panx1-400A individuals. Here, we demonstrated that Panx1-400C SNP predisposes to BMI-dependent endothelial dysfunction in non-obese subjects. This effect may be masked by excessive dysregulation of metabolic factors in obese individuals.

Differential activation of mouse and human Panx1 channel variants

“…Interestingly, the two hPanx1 variants responded differently to BzATP stimulation. We found that the Q5H variant which has been previously reported to form hyperactive channels [26, 34, 35] displayed significantly higher mean peak conductance than that recorded from hPanx1 when stimulated with the P2X7 receptor agonist. On the other hand, however, because the E390D variant was totally insensitive to this mode of stimulation, it is likely that the channels this variant forms are functionally dead, possibly like those of rs143240087 (R217H) which was reported to have dominant-negative effects [27].…”

“…In addition, missense variants in PANX1 have been associated with human diseases. These variants include rs1138800 (Q5H) [26, 34, 35] which leads to a hyperfunction of the channels and rs143240087 (R217H) which was reported to have a dominant-negative effect [27].…”

Connexins, Innexins, and Pannexins: From Biology to Clinical Targets

“…The more recently described pannexin channel proteins also seem to play a role in the vasculature, with multiple studies in mice pointing to a pathological role for Panx1. With regard to this, Molica et al [ 22 ] describe a single nucleotide polymorphism in Panx1 (Panx1-400A > C) that predisposes non-obese humans to body mass index-dependent endothelial dysfunction.…”