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Role of NF-κB and p38 MAPK activation in mediating angiotensin II and endothelin-1-induced stimulation in leptin production and cardiomyocyte hypertrophy

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Abstract

We recently identified leptin as a downstream factor mediating the hypertrophic effects of both angiotensin II and endothelin-1 in cardiomyocytes, an effect dependent on increased leptin biosynthesis, however, the mechanism for such increased leptin production is not known. This study was designed to elucidate the mechanisms underlying angiotensin II- and endothelin-1-stimulated synthesis in cultured ventricular myocytes. The hypertrophic effects of both angiotensin II (100 nM) and endothelin-1 (10 nM) were associated with increased leptin secretion and gene expression by 40 and 50 %, and 86 and 68 %, respectively. These effects were associated with significantly increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation by 34 and 52 %, as well as enhanced translocation of NF-κB into nuclei and also the NF-κB-DNA binding activity by 35 and 31 % induced by angiotensin II and endothelin-1, respectively. On their own, 24 h treatment with either angiotensin II or endothelin-1 increased cell surface area by 30 and 40 %, protein synthesis by 30 % and the α-skeletal actin gene by 53 and 68 %, respectively, indicating a robust hypertrophic effect whereas this was completely prevented by NF-κB inhibition. In addition, NF-κB inhibition significantly attenuated angiotensin II and endothelin-1-induced p38 MAPK activation whereas inhibition of p38 MAPK blocked both angiotensin II- and endothelin-1-induced increases in leptin secretion. The ability of both angiotensin II- and endothelin-1 to increase leptin production in cardiomyocytes and the resultant hypertrophic response are mediated by NF-κB and dependent on p38 MAPK activation.

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Acknowledgments

This study was supported by a grant (MOP62764) from the Canadian Institutes of Health Research. AK held a Postdoctoral Research Award from the Heart and Stroke Foundation of Canada during the course of these studies. MK is a Canada Research Chair in Experimental Cardiology.

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Author notes

  1. Ana Kilic

    Present address: Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, 53105, Bonn, Germany

  2. Sabzali Javadov

    Present address: Department of Physiology, School of Medicine, University of Puerto Rico, P.O. Box 365067, San Juan, PR, USA

Authors and Affiliations

  1. Department of Physiology & Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada

    Venkatesh Rajapurohitam, Ana Kilic, Sabzali Javadov & Morris Karmazyn

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  1. Venkatesh Rajapurohitam
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Correspondence to Morris Karmazyn.

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Rajapurohitam, V., Kilic, A., Javadov, S. et al. Role of NF-κB and p38 MAPK activation in mediating angiotensin II and endothelin-1-induced stimulation in leptin production and cardiomyocyte hypertrophy. Mol Cell Biochem 366, 287–297 (2012). https://doi.org/10.1007/s11010-012-1307-x

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