Posts Tagged ‘cardiospecific-kinase’

Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

Author and Curator: Larry H Bernstein, MD, FCAP



This report from Science Translational Medicine is about the finding that a cardiomyocyte-specific kinase limits reperfusion injury in acute coronary syndrome, a phenomenon driven by oxidative stress, protecting cardiac cells from further damage.

Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Limits Oxidative Stress, Injury, and Adverse Remodeling in the Ischemic Heart

Ronald J. Vagnozzi1,2,  Gregory J. Gatto Jr.3, Lara S. Kallander3, Nicholas E. Hoffman2, Karthik Mallilankaraman2, Victoria L. T. Ballard3, Brian G. Lawhorn3, …, and Thomas Force2,6,*
+ Author Affiliations
1Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA
2Center for Translational Medicine, and 6Cardiology Division, Temple University School of Medicine, Philadelphia, PA
3Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline, King of Prussia, PA
4Platform Technology and Sciences, GlaxoSmithKline, King of Prussia, PA
5Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8131, Japan.

Sci Transl Med 16 Oct 2013; 
5(207), p. 207ra141     http://dx.doi.org/10.1126/scitranslmed.3006479
Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I–interacting kinase (TNNI3K), a cardiomyocyte-specific kinase,
  1. promotes ischemia/reperfusion injury,
  2. oxidative stress,
  3. and myocyte death.
TNNI3K-mediated injury occurs
  • through increased mitochondrial superoxide production and
  • impaired mitochondrial function and is largely
  • dependent on p38 mitogen-activated protein kinase (MAPK) activation.

We developed a series of small-molecule TNNI3K inhibitors that

  1. reduce mitochondrial-derived superoxide generation,
  2. p38 activation, and
  3. infarct size
when delivered at reperfusion to mimic clinical intervention.
TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling.
Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS.  Pharmacologic TNNI3K inhibition would be cardiac-selective,
  • preventing potential adverse effects of systemic kinase inhibition.
Citation: R. J. Vagnozzi, G. J. Gatto, L. S. Kallander, N. E. Hoffman, K. Mallilankaraman, V. L. T. Ballard, B. G. Lawhorn, P. Stoy, J. Philp, A. P. Graves, Y. Naito, J. J. Lepore, E. Gao, M. Madesh, T. Force, Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Limits Oxidative Stress, Injury, and Adverse Remodeling in the Ischemic Heart. Sci. Transl. Med. 5, 207ra141 (2013).

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