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182 Expression Of Receptor-interacting Serine-threonine Kinases 1, 2 And 3 (ripks 1, 2 And 3) In The Heart And Their Regulation By Ischaemia/reperfusion Vs Oxidative Stress
  1. Samuel J Leonard,
  2. Benjamin Young J,
  3. Stephen Fuller J,
  4. Peter Sugden H,
  5. Angela Clerk
  1. University of Reading

Abstract

Introduction Receptor-interacting serine-threonine kinases 1, 2 and 3 (RIPK1, RIPK2 and RIPK3) are associated with death receptor signalling. In non-cardiac tissues, RIPK1 and RIPK3 respond to tumour necrosis factor α (TNFα) and signal to cytoprotection, apoptosis or necroptosis according to the cellular environment. In the heart, different degrees of oxidative stress can be cardioprotive, pro-apoptotic or induce necrosis, raising the question of the role(s) of RIPKs in the oxidative stress response. The few studies of RIPKs in the heart indicate that inhibition of RIPK1 prevents adverse remodelling following ischaemia/reperfusion in vivo, whereas RIPK2 signals to p38-MAPK.

Methods Expression of RIPK1, 2 and 3 mRNA (assessed using microarrays and quantitative qPCR) and protein (assessed by immunoblotting) was examined during cardiac development. Effects of oxidative stress (exemplified by H2O2) were assessed in neonatal rat ventricular myocytes (NRVMs). Effects of ischaemia/reperfusion (associated with oxidative stress) in the adult heart were assessed using ex vivo Langendorff perfused hearts.

Results Expression of RIPK1 and RIPK3 mRNAs was 1.3 to 1.8-fold higher in NRVMs compared to adult rat ventricular myocytes (ARVMs). This was reflected at the protein level in whole hearts. RIPK2 was ~1.8-fold higher in ARVMS than NRVMs, with a comparable increase in protein in adult hearts relative to neonatal hearts. RIPK4 was not detected. Concentrations of H2O2 that induce cardiac myocyte apoptosis resulted in reduced mobility of RIPK1 on Western blots, consistent with phosphorylation and activation. Furthermore, ischaemia/reperfusion induced profound downregulation of RIPK1 consistent with activation followed by caspase cleavage and degradation as occurs in other cells in response to TNFα.

Conclusions RIPKs 1, 2 and 3 are expressed at significant levels in adult and neonatal hearts. Activation of RIPK1 is likely to play a significant role in the cardiac myocyte response to oxidative stress, potentially mediating the switch between cardioprotection, apoptosis and necrosis.

  • protein kinases
  • cell death
  • heart

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