Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia.
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.
Affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.Show MeSH
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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).
Affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.