The Effects of the Human Germline Connexin40 Mutation A96S on Cardiac Physiology in the Intact Animal

Abstract

myocytes of diabetic rabbits as indicated by increase in co-immunoprecipitation (co-ip) of p47phox with p22phox subunits of NADPH oxidase and in glutathionylation of endothelial nitric oxide synthase (eNOS) (58± 6%) known to uncouple eNOS. Diabetes reduced co-ip of 1 Na+-K+ pump subunit with glutaredoxin 1 (Grx1) that reverses glutathionylation of proteins. Consistent with this, glutathionylation of the 1 subunit was increased (52± 9%) and electrogenic Na+-K+ pump current measured in voltage-clamped myocytes was reduced (0.26± 0.04 vs 0.44± 0.04 pA/pF). Administration of CL (40 g/kg/h) had no effect on glucose or insulin levels but reduced lipid peroxidation. It also reduced p47phox/p22phox co-ip, reduced glutathionylation of eNOS (51± 1%) and 1 pump subunit (74± 13%), increased Grx1/ 1 pump subunit co-ip and increased Na+-K+ pump current (0.6± 0.1 vs 0.26± 0.04 pA/pF). Diabetes inducedmolecular remodelling in anoxidative pathway that is determinant of the functionally important oxidativemodification of Na+–K+ pump. Reversal of these changes by 3 AR stimulation suggests that 3 ARagonists may have cardiovascular protective effects in diabetes. http://dx.doi.org/10.1016/j.hlc.2013.05.239