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MAP4K4 MEDIATES CARDIOMYOCYTE CELL DEATH AND POTENTIATES A HEART FAILURE PHENOTYPE
  1. LR Fiedler1,
  2. M Jenkins1,
  3. E Maifoshie1,
  4. M Harada1,
  5. DJ Stuckey2,
  6. W Song3,
  7. R Sampson1,
  8. SE Harding1,
  9. MD Schneider1
  1. 1NHLI, Imperial College London
  2. 2Centre for Advanced Biomedical Imaging (CABI), University College London
  3. 3Lee Kong Chian School of Medicine, Nanyang Technological Unversity, Singapore

Abstract

Rationale Cardiomyocyte cell death plays a causal role in heart failure therefore its inhibition poses a promising therapeutic approach. However, investment is undermined due to poor translation and cardiotoxicity. Here, we describe validation of a potential target; mitogen activated protein 4 kinase kinase kinase kinase (MAP4K4).

Methodology/Results 4 weeks pressure overload (TAC; transverse aortic constriction) in alphaMyHC-MAP4K4 mice (cardiomyocyte-specific over-expression) induced apoptosis (3.60 %+1.01 TUNEL-positive cardiomyocytes, n=5, p<0.05 to wildtype (WT) littermates; 0.53 %+0.19, n=5). Peri-vascular fibrosis and upregulation of autophagy markers Beclin1 and LC3 (associated with heart failure) was evident only in TG-TAC mice (p<0.05 to WT-TAC). Systolic function assessed by pressure-volume loops (shams n=6, TAC-TG n=9, TAC-WT n=10) showed unaffected contractility and compliance in WT-TAC mice although relaxation was impaired (Tau, p<0.05). In contrast, TG-TAC mice had significantly impaired compliance (Emax, p<0.01), contractility (Ees-ESPVR, p<0.01) and relaxation (Tau, p<0.01).

Inhibition of MAP4K4, by siRNA-mediated knockdown or pharmacologically (selective in-house novel compound; 5 out of 141 kinases inhibited) was cardioprotective in rat neonatal and human iPSC-derived cardiomyocytes subjected to oxidative stress (H202) or C2-ceramide (measured by loss of membrane integrity, Caspase 3 activity, hypodiploid DNA).

Conclusions MAP4K4 drives cardiomyocyte cell death and dysfunction, thus poses an attractive target in heart failure. Our novel compound, validated in human and mouse models, represents a start-point for further development with improved translational potential.

  • CARDIAC PROCEDURES AND THERAPY

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