Abstract 1555: Parasympathetic Response of the Heart is Attenuated in Sterol Response Element Binding Protein Knockout Mice
Prior studies from our laboratory have demonstrated that culture of embryonic chick atrial myocytes in the absence of LDL cholesterol markedly increased their negative chronotropic response to carbamylcholine which involves the stimulation of IKAch via the activation of an inward rectifying K+ channel a heterodimer of GIRK1and GIRK4. Lipid lowering stimulated the sterol regulatory element binding protein (SREBP) in atrial myocytes suggesting that lipid metabolism might play a role in regulating the parasympathetic response of the heart. Here we demonstrate that SREBP1-KO mice have reduced parasympathetic response of the heart. EKG transmitters (DSI) were implanted into 6 month old SREBP1-KO (deficient in SREBP1a and 1c) and WT mice and EKGs recorded using DataquestART software. The negative chronotropic response to carbamylcholine in SREBP1-KO mice was markedly decreased compared to WT: duration of bradycardia, 5.6±1.7 min (N=7) compared to 9.9±1.3 min (N=8) in WT, p<0.05; 80% recovery time from bradycardia, 5.2±0.79 min (N=7), compared to 10.5±1.6 min (N=8) in WT, P<0.05. Western blot analysis of extracts from atria of SREBP1-KO mice demonstrated a 48±7% decrease (N=5, p<0.03) in expression of GIRK1 compared to WT. Furthermore atrial myocytes acutely dissociated from adult SREBP1-KO mice demonstrated markedly reduced carbamylcholine-activated inward rectifying current with characteristics of IKAch with a peak value of -192±21 pA/pF (N=7) compared to −413±33 pA/pF (N=7, p<0.001) in cells from WT mice. In order to determine whether the reduction in IKAch in cells from SREBP1-KO mice was specifically due to the deficiency in SREBP1, atrial myocytes dissociated from adult SREBP1-KO mice were infected with adenovirus expressing either GFP or SREBP1c. Atrial myocytes infected with AdGFP demonstrate IKAch with a peak value of −158±35 pA/pF (N=7) similar to that from uninfected cells. Adenoviral expression of SREBP1c markedly increased IKAch in cells from SREBP1-KO mice to −317±27 pA/pF (N=7, p<0.004). These data support the conclusion that SREBP plays an important role in the regulation of the parasympathetic response of the heart and might constitute a novel link between lipid metabolism and autonomic regulation of the heart.