Novel role for caspase-activated DNase in the regulation of pathological cardiac hypertrophy

Kai Huang, Lu Gao, Kun Huang, Ding Sheng Jiang, Xiaoxiong Liu, Dan Huang, Hongliang Li, Xiao Dong Zhang

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Caspase-activated DNase (CAD) is a double-strand-specific endonuclease that is responsible for the cleavage of nucleosomal spacer regions and subsequent chromatin condensation during apoptosis. Given that several endonucleases (eg, DNase I, DNase II, and Endog) have been shown to regulate pathological cardiac hypertrophy, we questioned whether CAD, which is critical for the induction of DNA fragmentation, plays a pivotal role in pressure overload-elicited cardiac hypertrophy. A CAD-knockout mouse model was generated and subjected to aortic banding for 8 weeks. The extent of cardiac hypertrophy was evaluated by echocardiography and pathological and molecular analyses. Our results demonstrated that the disruption of CAD attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, transgenic mice with cardiac-specific overexpression of CAD showed an aggravated cardiac hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 was significantly reduced in the CAD-knockout hearts compared with the control hearts; however, they were greatly increased in the CAD-overexpressing hearts after aortic banding. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes after treatment with angiotensin II for 48 hours. These data indicate that CAD functions as a necessary modulator of the hypertrophic response by regulating the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 signaling pathway in the heart. Our study suggests that CAD might be a novel target for the treatment of pathological cardiac hypertrophy and heart failure.

Original languageEnglish (US)
Pages (from-to)871-881
Number of pages11
JournalHypertension
Volume65
Issue number4
DOIs
StatePublished - Apr 20 2015

Keywords

  • CAD
  • ERK1/2
  • MEK1/2
  • apoptosis
  • cardiac hypertrophy

ASJC Scopus subject areas

  • Internal Medicine

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