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Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

ABSTRACT: Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.

SUBMITTER: Li C

PROVIDER: S-EPMC4212990 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

Li Chao C Zhang Yu Yao YY Frieler Ryan A RA Zheng Xiao Jun XJ Zhang Wu Chang WC Sun Xue Nan XN Yang Qing Zhen QZ Ma Shu Min SM Huang Baozhuan B Berger Stefan S Wang Wang W Wu Yong Y Yu Ying Y Duan Sheng Zhong SZ Mortensen Richard M RM

PloS one 20141029 10

Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuate ...[more]

PMID: 25354087

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Project description:ObjectiveAlthough hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of angiotensin II type 1 receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model.Approach and resultsTwo weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation and thickening of the medial and adventitial layers of the aorta. There was significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density attributable to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC-induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC-induced adventitial hyperplasia, collagen accumulation, and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas were effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked extracellular signal-regulated kinase activation and reactive oxygen species production in the TAC ascending aorta.ConclusionsInhibition of the angiotensin II type 1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased transforming growth factor-β1 expression, adventitial Smad2 signaling, and collagen accumulation. These results help to delineate the aortic transforming growth factor-β signaling that is dependent and independent of the angiotensin II type 1 receptor after TAC.

Dataset Information

Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

Publications

Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

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