Serum-glucocorticoid regulated kinase 1 regulates alternatively activated macrophage polarization contributing to angiotensin II-induced inflammation and cardiac fibrosis.

Abstract

OBJECTIVE:

Inflammatory responses play a pivotal role in the pathogenesis of hypertensive cardiac remodeling. Macrophage recruitment and polarization contribute to the development of cardiac fibrosis. Although serum-glucocorticoid regulated kinase 1 (SGK1) is a key mediator of fibrosis, its role in regulating macrophage function leading to cardiac fibrosis has not been investigated. We aimed to determine the mechanism by which SGK1 regulates the cardiac inflammatory process, thus contributing to hypertensive cardiac fibrosis.

METHODS AND RESULTS:

After angiotensin II infusion in mice, cardiac hypertrophy and fibrosis developed in wild-type but not SGK1 knockout mice, with equal levels of hypertension in both groups. Compared with wild-type hearts, SGK1 knockout hearts showed less infiltration of leukocytes and macrophages. Importantly, SGK1 deficiency led to decreased proportion of alternatively activated (M2) macrophages and increased levels of profibrotic cytokines. Angiotensin II infusion induced phosphorylation and nuclear localization of signal transducer and activator of transcription 3 (STAT3) whereas SGK1 knockout hearts showed this effect attenuated. In a 3-dimensional peptide gel culture, inhibition of STAT3 suppressed differentiation into M2 macrophages. Coculture of macrophages with cardiac fibroblasts in 3-dimensional peptide gel stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, SGK1 knockout mice with macrophage deficiency showed reduced fibroblast-to-myofibroblast transition.

CONCLUSIONS:

SGK1 may play an important role in macrophage recruitment and M2 macrophage activation by activating the STAT3 pathway, which leads to angiotensin II-induced cardiac fibrosis.

• Authors: Min Yang, Jiao Zheng, Yanjv Miao, Ying Wang, Wei Cui, Jun Guo, Shulan Qiu, Yalei Han, Lixin Jia, Huihua Li, Jizhong Cheng, Jie Du
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 7 Pg. 1675-86 (Jul 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22556335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immediate-Early Proteins
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Angiotensin II
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase
• Leukocyte Common Antigens
• Ptprc protein, mouse

Topics

• Angiotensin II (pharmacology)
• Animals
• Cell Polarity
• Cells, Cultured
• Fibrosis
• Immediate-Early Proteins (physiology)
• Inflammation (etiology)
• Leukocyte Common Antigens (analysis)
• Macrophage Activation
• Macrophages (cytology)
• Male
• Mice
• Myocardium (enzymology, pathology)
• Protein Serine-Threonine Kinases (physiology)
• STAT3 Transcription Factor (physiology)