Article Text

GW24-e0525 The role of caspase-associated recruitment domain 9 in cardiac inflammation and fibrosis caused by hypertension
  1. Ren Jingyuan1,2,
  2. Min Yang1,2,
  3. Jie Du1,2
  1. 1Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing
  2. 2Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China


Objectives The aim of this study is to examine the role of CARD9 in inflammation and cardiac fibrosis induced by Ang II infusion, and to elucidate the mechanism that is responsible for activation of NF-κB in macrophages induced by Ang II infusion.

Methods Two-month-old CARD9-deficient (CARD9-/-) and wild-type (WT) male mice were infused with Ang II (1,500 ng/kg/min) or saline for 7 days. Systolic blood pressure was measured by the tail-cuff system. Animals were killed 7 days after Ang II or saline infusion. Heart sections were stained with hematoxylin and eosin and Masson trichrome and examined by immunohistochemistry, and activity and protein levels were measured in macrophages obtained from mice.

Results The genotyping of CARD9-/- mice was confirmed by PCR. Systolic blood pressure was markedly increased in both WT and CARD9-/- mice after Ang II infusion. WT mice with Ang II infusion showed a marked increase in CARD9+ macrophages in the heart. Knockout of CARD9 showed significantly suppressed Ang II infusion-induced macrophage infiltration and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β) (P < 0.001) and c (CTGF) (P < 0.001). The heart sections stained with Masson trichrome showed that Ang II infusion significantly increased cardiac fibrotic areas in Ang II-treated WT mice as compared with untreated WT mice (P < 0.001). However, in CARD9-/- mice, the fibrotic areas were significantly smaller than in WT mice with Ang II treatment (P < 0.01). Moreover, immunohistochemistry demonstrated that Ang II infusion-induced the increase in protein levels of Collagen I (P < 0.05) and TGF-β (P < 0.05) in WT mice were markedly suppressed in CARD9-/- mice. The increase in protein expression of α-SMA induced by Ang II infusion in WT mice was significantly reduced in CARD9-/- mice (P < 0.01). Furthermore, Ang II-induced activation of nuclear factor-κB (NF-κB), JNK and p38 mitogenactivated protein kinases (MAPKs) in WT macrophages were reduced in CARD9-/- macrophages.

Conclusions We revealed an important role of CARD9 in Ang II infusion-induced cardiac remodelling. CARD9 deficiency inhibited inflammatory cells infiltration, expression of proinflammatory cytokines, accumulation of myofibroblasts, and cardiac fibrosis. These effects are a result of inhibiting the activation of NF-κB and MAPKs.

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