Oxidative and Inflammation

The long-term goal of this research proposes to understand reactive oxygen species (ROS)-induced oxidative stress and inflammatory signaling mechanisms altering sarcomeric protein function and leading to heart failure and dilated cardiomyopathy following either ischemia-reperfusion injury or mutations in the MYBPC3 gene.

The development of acute and chronic heart failure (HF) has been associated with increased inflammation and oxidative stress. Oxidative stress results from imbalances between ROS and antioxidant reserves, which can lead to elevated cardiac remodeling and functional HF. Inflammation produced by oxidative stress has been indicated as causative of many chronic human diseases. Dilated cardiomyopathy has been identified as the chronic phase of an inflammatory disease of the myocardium. In 30 - 40% of dilated cardiomyopathy cases, endomyocardial biopsy reveals fibrosis and myocyte loss, with immunohistochemical analysis showing chronic inflammation consistent with myocarditis. However, the association between oxidative stress/inflammation and genetic DCM in relation to sarcomere protein dysfunction has not been well defined. 

Our current studies are also focused on elucidating the effects of glutathionylation on sarcomeric proteins, in particular cardiac myosin binding protein-C, in the clinical context of dysfunction following ischemia- reperfusion injury, using mouse models. Preventing cMyBP-C glutathionylation represents a viable therapeutic approach to improve cardiac function post-ischemia reperfusion injury.

References:

• Wang L, Ji X, Barefield D, Sadayappan S, Kawai M. Phosphorylation of cMyBP-C affects contractile mechanisms in a site-specific manner. Biophys J. 2014 Mar 4;106(5):1112-22.
• Khairallah RJ and Sadayappan S. Finding the Missing Link: Disulfide-containing proteins via a high- throughput proteomics approach. Proteomics. 2013 13(22):3245-6
• Sadayappan S, de Tombe PP. Cardiac myosin binding protein-C as a central target of cardiac sarcomere signaling: a special mini review series. Pflugers Arch. 2014 466(2):195-200.
• Kuster DW, Sequeira V, Najafi A, Boontje N, J M Wijnker P, Witjas-Paalberends R, Marston S, Dos Remedios CG, Carrier L, Demmers JA, Redwood CS, Sadayappan S,van der Velden J. GSK3β phosphorylates newly identified site in the Pro-Ala Rich region of cardiac myosin binding protein-C and alters cross-bridge cycling kinetics in human. Circ Res. 2013 Feb 15;112(4):633-9.
• Govindan S, McElligott A, Muthusamy S, Nair N, Barefield D, Greis KD, Martin JL, Gongora E, Luther PK, Winegrad S, Henderson KK and Sadayappan S,Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction. J Mol Cell Cardiol. 2012; 52(1):154-64.
• Sadayappan S, Gulick J, Martin LA, Osinska H, Barefield D, Cuello C, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JM, Brown JH, Bers DM, Molkentin JD and Robbins J. Critical Function of Ser-282 in Cardiac myosin binding protein-C phosphorylation and cardiac function. Circ Res. 2011 109(2):141-50.
• Cuello F, Bardswell SC, Haworth RS, Ehler E, Sadayappan S, Kentish JC and Avkiran M. A novel role for p90 ribosomal S6 kinase in the regulation of cardiac function J Biol Chem. 2011 18;286(7):5300-10.
• Copeland O, Sadayappan S, Messer AE, van der Velden J, Stienen GJM, Marston SB. Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. J Mol Cell Cardiol, 2010 49(6):1003-11.