User Settings
Article10.1161/circ.124.suppl_21.a9943

Abstract 9943: Prevention and Reversal of Hypertrophy Through a Novel Drug-Like Compound That Inhibits Local Calcium Oscillations in a Pmca4/calcineurin Microdomain

Tamer Mohamed,Delvac Oceandy,Riham Abouleisa,Min Zi,Sukhpal Prehar,Florence Baudoin+2 more-2011-11-22-Circulation
0

TL;DRAbstract

In pathological hypertrophy, the calcium/calmodulin dependent phosphatase calcineurin has been shown to transmit upstream calcium signals through dephosphorylation of the transcription factor NFAT which subsequently translocates to the nucleus and initiates a hypertrophic gene programme. We have previously shown that plasma membrane calcium ATPase isoform 4 (PMCA4) binds to calcineurin when overexpressed in HEK293 cells. We here investigated whether targeting PMCA4 by genetic or pharmacological strategies provides novel opportunities for the reduction of cardiac hypertrophy through modulation of calcineurin. Germline PMCA4 ablation resulted in the attenuation of pathological hypertrophy in response to pressure overload (Heart weight /tibia length ratio after transverse aortic constriction (TAC), PMCA4-/-: 6.74 ± 0.33 mg/mm vs WT: 8.34 ± 0.88 mg/mm, P10). Mechanistically, PMCA4 ablation led to a significant reduction in calcineurin at the sarcolemma as shown by Western blot and electron

Chat with Paper

AI Agents for this Paper

In pathological hypertrophy, the calcium/calmodulin dependent phosphatase calcineurin has been shown to transmit upstream calcium signals through dephosphorylation of the transcription factor NFAT which subsequently translocates to the nucleus and initiates a hypertrophic gene programme. We have previously shown that plasma membrane calcium ATPase isoform 4 (PMCA4) binds to calcineurin when overexpressed in HEK293 cells. We here investigated whether targeting PMCA4 by genetic or pharmacological strategies provides novel opportunities for the reduction of cardiac hypertrophy through modulation of calcineurin. Germline PMCA4 ablation resulted in the attenuation of pathological hypertrophy in response to pressure overload (Heart weight /tibia length ratio after transverse aortic constriction (TAC), PMCA4-/-: 6.74 ± 0.33 mg/mm vs WT: 8.34 ± 0.88 mg/mm, P10). Mechanistically, PMCA4 ablation led to a significant reduction in calcineurin at the sarcolemma as shown by Western blot and electron

Keywords

CalcineurinLipid microdomainMedicineCalciumDrugInternal medicinePharmacologyBiochemistry

Chat

Click to start Chat