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Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia.

Zhang T, Lu X, Beier F, Feng Q - J. Cell. Mol. Med. (2010)

Bottom Line: Furthermore, inhibition of PI3K and Rac1 activity decreased LPS-induced superoxide generation which was associated with a significant reduction in ERK1/2 phosphorylation.Deficiency in Rac1 significantly decreased myocardial TNF-α expression and improved cardiac function during endotoxemia.We conclude that PI3K-mediated Rac1 activation is required for induction of TNF-α expression in cardiomyocytes and cardiac dysfunction during endotoxemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

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Related in: MedlinePlus

TNF-α expression in Rac1f/f and Rac1–/– adult mouse myocardium during endotoxemia. (A) Rac1 protein expression in heart, skeletal muscle and lungs in Rac1f/f and Rac1–/– mice as determined by Western blot analysis. TNF-α mRNA (B) and protein (C) levels in Rac1f/f and Rac1–/– heart tissues were measured after 2 and 4 hrs of LPS treatment (2 mg/kg, i.p.). Data are means ± S.E.M., n = 3 to 10 per group. **P < 0.01 versus sham Rac1f/f, ††P < 0.01 versus LPS Rac1f/f.
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fig07: TNF-α expression in Rac1f/f and Rac1–/– adult mouse myocardium during endotoxemia. (A) Rac1 protein expression in heart, skeletal muscle and lungs in Rac1f/f and Rac1–/– mice as determined by Western blot analysis. TNF-α mRNA (B) and protein (C) levels in Rac1f/f and Rac1–/– heart tissues were measured after 2 and 4 hrs of LPS treatment (2 mg/kg, i.p.). Data are means ± S.E.M., n = 3 to 10 per group. **P < 0.01 versus sham Rac1f/f, ††P < 0.01 versus LPS Rac1f/f.

Mentions: To study the role of Rac1 in myocardial depression during endotoxemia in vivo, we generated cardiac-specific Rac1 knockout mice using Cre-loxP recombination as described in the methods. Our data showed that the Rac1 protein was selectively knocked down in the heart but not in the skeletal muscle and lungs in Rac1–/– mice (Fig. 7A). Rac1–/– and Rac1f/f mice were treated with vehicle or LPS (2 mg/kg, i.p.). Our data demonstrated that LPS-induced myocardial TNF-α mRNA and protein levels were significantly decreased (P < 0.01, Fig. 7B and C). After 2 hrs of LPS in vivo treatment, cardiac function was determined using the Langendorff preparation. The rate of contraction and relaxation, heart rate and heart work were significantly reduced in both Rac1f/f and Rac1–/– mice after endotoxemia (P < 0.05, Fig. 8). However, compared with Rac1f/f mice, heart work and rate of contraction (+dF/dtmax) were significantly increased in Rac1–/– mice (P < 0.05, Fig. 8).


Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia.

Zhang T, Lu X, Beier F, Feng Q - J. Cell. Mol. Med. (2010)

TNF-α expression in Rac1f/f and Rac1–/– adult mouse myocardium during endotoxemia. (A) Rac1 protein expression in heart, skeletal muscle and lungs in Rac1f/f and Rac1–/– mice as determined by Western blot analysis. TNF-α mRNA (B) and protein (C) levels in Rac1f/f and Rac1–/– heart tissues were measured after 2 and 4 hrs of LPS treatment (2 mg/kg, i.p.). Data are means ± S.E.M., n = 3 to 10 per group. **P < 0.01 versus sham Rac1f/f, ††P < 0.01 versus LPS Rac1f/f.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822624&req=5

fig07: TNF-α expression in Rac1f/f and Rac1–/– adult mouse myocardium during endotoxemia. (A) Rac1 protein expression in heart, skeletal muscle and lungs in Rac1f/f and Rac1–/– mice as determined by Western blot analysis. TNF-α mRNA (B) and protein (C) levels in Rac1f/f and Rac1–/– heart tissues were measured after 2 and 4 hrs of LPS treatment (2 mg/kg, i.p.). Data are means ± S.E.M., n = 3 to 10 per group. **P < 0.01 versus sham Rac1f/f, ††P < 0.01 versus LPS Rac1f/f.
Mentions: To study the role of Rac1 in myocardial depression during endotoxemia in vivo, we generated cardiac-specific Rac1 knockout mice using Cre-loxP recombination as described in the methods. Our data showed that the Rac1 protein was selectively knocked down in the heart but not in the skeletal muscle and lungs in Rac1–/– mice (Fig. 7A). Rac1–/– and Rac1f/f mice were treated with vehicle or LPS (2 mg/kg, i.p.). Our data demonstrated that LPS-induced myocardial TNF-α mRNA and protein levels were significantly decreased (P < 0.01, Fig. 7B and C). After 2 hrs of LPS in vivo treatment, cardiac function was determined using the Langendorff preparation. The rate of contraction and relaxation, heart rate and heart work were significantly reduced in both Rac1f/f and Rac1–/– mice after endotoxemia (P < 0.05, Fig. 8). However, compared with Rac1f/f mice, heart work and rate of contraction (+dF/dtmax) were significantly increased in Rac1–/– mice (P < 0.05, Fig. 8).

Bottom Line: Furthermore, inhibition of PI3K and Rac1 activity decreased LPS-induced superoxide generation which was associated with a significant reduction in ERK1/2 phosphorylation.Deficiency in Rac1 significantly decreased myocardial TNF-α expression and improved cardiac function during endotoxemia.We conclude that PI3K-mediated Rac1 activation is required for induction of TNF-α expression in cardiomyocytes and cardiac dysfunction during endotoxemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Show MeSH
Related in: MedlinePlus