Proinflammatory Protein CARD9 Is Essential for Infiltration of Monocytic Fibroblast Precursors and Cardiac Fibrosis Caused by Angiotensin II Infusion

BACKGROUND: Angiotensin II (Ang II)–induced cardiac remodeling with the underlying mechanisms involving inflammation and fibrosis has been well documented. Cytosolic adaptor caspase recruitment domain 9 (CARD9) has been implicated in the innate immune response. We aimed to examine the role of CARD9 in inflammation and cardiac fibrosis induced by Ang II. 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. 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: WT mice with Ang II infusion showed a marked increase in CARD9(+) macrophages in the heart, but CARD9(−/−) mice showed significantly suppressed macrophage infiltration and expression of proinflammatory cytokines, including interleukin-1β (IL-1β) and connective tissue growth factor (CTGF). Importantly, Ang II–induced cardiac fibrosis (extracellular matrix and collagen I deposition) was diminished in CARD9(−/−) hearts, as was the expression of transforming growth factor-β (TGF-β) and level of myofibroblasts positive for α-smooth muscle actin (α-SMA). Furthermore, Ang II activation of nuclear factor-κB (NF-κB), JNK and p38 mitogen-activated protein kinases (MAPKs) in WT macrophages was reduced in CARD9(−/−) macrophages. CONCLUSION: CARD9 plays an important role in regulating cardiac inflammation and fibrosis in response to elevated Ang II.