A new study published this month by Dr Olga Eleftheriadou and Dr Andrew Snabaitis shows for the first time the importance of a family of proteins called Type 2A protein phosphatases in cardiac hypertrophy.
Type 2A protein phosphatases are a ubiquitous family of enzymes that are characterized by the catalytic subunits PP2AC, PP4C and PP6C which when activated, remove phosphate (dephosphorylate) from serine/threonine amino acids of a substrate protein. This dephosphorylation of substrate proteins can consequently alter a protein’s activity and/or cellular localization. Type 2A protein phosphatases are also regulated by a number of non-catalytic regulatory proteins such as alpha4. Cardiac physiology and pathological hypertrophy/heart failure are regulated by the phosphorylation status of many proteins, which is partly controlled by a poorly defined type 2A protein phosphatase-alpha4 intracellular signalling axis.
This study describes novel observations that type 2A C-subunit expression in the healthy and diseased (hypertrophied) myocardium differs significantly. Cellular content of alpha4 was significantly elevated in hypertrophied myocardium, however its association with PP2AC or PP6C was either unchanged or significantly reduced, respectively. The phosphorylation status of phospholemman, an inhibitory accessory subunit of the Na+/K+-ATPase (sodium pump) which is dephosphorylated in hypertrophied myocardium, was regulated by PP2AC alpha, PP2AC beta and PP4C, but not by PP6C in cardiomyocytes. DNA damage induced by oxidant stress was not regulated by PP6C but was highly dependent on the cardiomyocyte content of alpha4 protein. In addition, depletion of alpha4 protein in cardiomyocytes induced a significant loss of the core histone H2AX in cardiomyocytes, a response that is indicative of cell stress and ongoing cellular DNA damage repair. This study demonstrates the significance and altered activity of the type 2A protein phosphatase-alpha4 complex in healthy and hypertrophied myocardium.
The study is published in the journal Basic Research Cardiology.