Abcc6 Deficiency Causes Increased Infarct Size and Apoptosis in a Mouse Cardiac Ischemia-Reperfusion Model

Objective— ABCC6 genetic deficiency underlies pseudoxanthoma elasticum (PXE) in humans, characterized by ectopic calcification, and early cardiac disease. The spectrum of PXE has been noted inAbcc6 -deficient mice, including dystrophic cardiac calcification. We tested the role ofAbcc6 in response to cardiac ischemia-reperfusion (I/R) injury.Methods and Results— To determine the role ofAbcc6 in cardioprotection, we induced ischemic injury in mice in vivo by occluding the left anterior descending artery (30 minutes) followed by reperfusion (48 hours). Infarct size was increased inAbcc6 -deficient mice compared with wild-type controls. Additionally, an Abcc6 transgene significantly reduced infarct size on the background of a naturally occurringAbcc6 deficiency. There were no differences in cardiac calcification following I/R, but increased cardiac apoptosis was noted inAbcc6 -deficient mice. Previous studies have implicated the bone morphogenetic protein (BMP) signaling pathway in directing calcification, and here we showed that the BMP responsive transcription factors pSmad1/5/8 were increased in hearts ofAbcc6 mice. Consistent with this finding, BMP4 and BMP9 were increased and activin receptor-like kinase-2 and endoglin were downregulated in cardiac extracts fromAbcc6 -deficient mice versus controls.Conclusion— These data identifyAbcc6 as a novel modulator of cardiac myocyte survival after I/R. This cardioprotective mechanism may involve inhibition of the BMP signaling pathway, which modulates apoptosis.