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The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on CaMKIIδ in TAC-Induced Myocardial Hypertrophy

Jianan Qian1, Jingjing Zhang1,2, Ji Cao1

  • 1School of Pharmacy, Nantong University, Nantong 226001, China.

International Journal of Molecular Sciences
|October 14, 2023
PubMed

Insights

Receptor-interacting protein kinase 3 (RIPK3) deficiency alleviates myocardial hypertrophy by inhibiting necroptosis and calcium/calmodulin-dependent protein kinase II (CaMKII) activation. Targeting RIPK3 offers a potential therapeutic strategy for treating cardiac hypertrophy.

Area of Science:

  • Cardiovascular Biology
  • Cell Death Mechanisms
  • Molecular Cardiology

Background:

  • Necroptosis, a regulated form of cell death, is orchestrated by RIPK1 and RIPK3.
  • Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a RIPK3 substrate implicated in cardiovascular diseases via alternative splicing.
  • Myocardial hypertrophy involves complex cellular processes, including cell death and altered gene expression.

Purpose of the Study:

  • To investigate the role and mechanism of necroptosis and CaMKIIδ alternative splicing in myocardial hypertrophy.
  • To determine if RIPK3 deficiency or modulation impacts cardiac function and cellular damage in a mouse model of hypertrophy.
  • To explore the therapeutic potential of targeting RIPK3 in myocardial hypertrophy.

Main Methods:

  • Established myocardial hypertrophy in wild-type and RIPK3 knockout mice using transverse aortic constriction (TAC).
  • Assessed cardiac function (echocardiography, cardiac index), myocardial cell size, gene expression, and tissue damage.
  • Analyzed necroptosis markers (RIPK3, RIPK1, p-MLKL), splicing factors (ASF/SF2, SC-35), CaMKII activation, oxidative stress, and mitochondrial integrity. Investigated RIPK3 gene therapy using AAV vectors.

Main Results:

  • RIPK3 deficiency significantly attenuated cardiac dysfunction, myocardial injury, necroptosis, and CaMKII activation in TAC-induced hypertrophy.
  • Recombinant adeno-associated virus (AAV)-mediated RIPK3 delivery reversed cardiac dysfunction, damage, and CaMKII activation.
  • TAC surgery exacerbated necroptosis and CaMKII activation, which were mitigated by RIPK3 modulation.

Conclusions:

  • RIPK3 plays a critical role in the pathogenesis of myocardial hypertrophy by promoting necroptosis and CaMKII activation.
  • Targeting RIPK3, either through genetic deficiency or AAV-mediated gene therapy, demonstrates a protective effect against cardiac hypertrophy.
  • RIPK3 emerges as a promising molecular target for the prevention and treatment of myocardial hypertrophy.
Keywords:
CaMKIIδRIPK3alternative splicingmyocardial hypertrophynecroptosis

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