It is anticipated that by controlling the CaMKII δ in PRMT1, one can prevent/manage cardiac disease and heart failure
Prof. KANG, JONG SUN
Cardiac disease is one of the most common adult diseases and a leading cause of death worldwide. The increasing rate of cardiac disorder is due to westernized lifestyle and aging population. It is an urgent matter to develop a method of treatment by researching the pathogenesis of cardiac disorders.
The cause of most cardiac disorders roots from the regenerating process of the cardiomyocyte. When the cardiomyocyte cannot self-regenerate, it chooses to extend or increase in size, resulting ‘Cardiac hypertrophy’. Cardiac hypertrophy is kind of an adaptive response to physiological and pathological stimuli. However, pathological cardiac hypertrophy leads to heart failure.
This study exhibited that mice with deficiency of cardiac PRMT1 showed a rapid progression to dilated cardiomyopathy and heart failure within 2 months of birth. Heart failure was accompanied with cardiomyocyte hypertrophy and fibrosis. From this, the research team discovered that PRMT1 is essential for the maintenance and survival of the cardiac function.
CaMKII δ(Calcium/calmodulin-dependent protein kinase II δ), which was identified as the main target of this study has been linked with maintenance of Ca2+ homeostasis by phosphorylating various proteins important for excitation–contraction coupling and cell survival including ion channels. Thus, they proved that dysregulation of CaMKII δ is closely linked with myocardial hypertrophy and heart failure. However, the mechanism that regulates CaMKII activity is still in need for further research.
The most important finding of this study was the fact that the protein arginine methyltransferase 1 (PRMT1) is essential for preventing cardiac CaMKII hyperactivation. The level of active CaMKII is significantly elevated in PRMT1-deficient hearts or cardiomyocytes. PRMT1 interacts with methylates CaMKII, leading to the inhibition. Accordingly, pharmacological inhibition of CaMKII restores contractile function in PRMT1-deficient mice. Thus, our study suggests that PRMT1 is a critical regulator of CaMKII to maintain cardiac function and potential therapeutic target of cardiac disease.
Figure 1. Discovered that PRMT1 is the main factor that controls the level of stress that causes hypertrophy
Figure 2. Identified that PRMT1 controls the activation of CaMKII δ