Inhibiting the protein involved in Phosphorylation may treat Heart disorders

The researchers at Johns Hopkins University School of Medicine are conducting a new study for manufacturing personalized medicine with the help of protein markers for varied level of Phosphorylation.

A form of heart disease known as heart failure with preserved ejection fraction (the amount of blood squeezed out when the heart contracts) impairs the heart’s ability to quickly and efficiently relax between “beats,” overworking the organ. The disease is estimated to impair circulation in more than 23 million people worldwide. Patients with ejection fraction issue preserved at baseline have particular difficulty when they try to increase their activity or exercise unlike the usual issue of shortness of breath that occurs in the other types of heart disorders.

The researchers found that heart failure was associated with changes in heart muscle cells through altered phosphorylation in the heart muscle protein cardiac troponin I (cTnI), which helps regulate heart contraction. They also found that phosphorylation at a specific site on the protein, cTnI Serine 199, in humans was nearly twofold higher in people with heart failure than those without heart failure. This study urged them to proceed with research in detail.

The Study

In order to find out whether the increase of cardiac troponin I (cTnI) was directly involved or only linked to impaired function, the researchers created two strains of mice, one with hyperphosphorylation of the mouse-analogous cTnI Serine 199 site and one in which phosphorylation of the site was turned off altogether.

  • Results of first phase of the experiment – At baseline the mice with hyperphosphorylation on this specific site experienced a longer time to heart relaxation and lower left ventricular peak filling rate (depressed diastolic function), but the amount of blood ejected during contraction was normal.
  • Results of second phase of the experiment -The researchers then stimulated both strains of mouse hearts with adrenaline to assess the impact of increased demand on the hearts. The mice with hyperphosphorylation had very limited ability to increase the ejection of blood from the heart compared to the controls in response to adrenaline. However, the mice with hyperphosphorylation did show some improvement in relaxation, though relaxation remained slower than controls at peak drug effect.
  • Results of the third phase of the experiment – The researchers then subjected both sets of mice to brief periods of reduced oxygen flow to the heart and then restored the flow of oxygen. It was observed that the hearts of mice with hyperphosphorylation were protected from this form of stress.
  • Current phase of the experiment – Researchers are studying drugs that inhibit phosphorylation of proteins at specific sites. A specific enzyme called protein kinase C phosphorylates the cTnI 199 site.




[2] Li, Y., Zhu, G., Paolocci, N., Zhang, P., Takahashi, C., Okumus, N., . . . Murphy, A. M. (2017). Heart Failure–Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo. Circulation: Heart Failure, 10(9). doi:10.1161/circheartfailure.117.003850

[3] Lu, Q., Hinken, A. C., Patrick, S. E., Solaro, R. J., & Kobayashi, T. (2010). Phosphorylation of Cardiac Troponin I at Protein Kinase C Site Threonine 144 Depresses Cooperative Activation of Thin Filaments. Journal of Biological Chemistry, 285(16), 11810-11817. doi:10.1074/jbc.m109.055657


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