Introduction
The heart is not big, but this small organ will beat more than 2.5 billion times in an average lifetime, providing us with the contractile power needed for life and never stopping to rest. Heart failure (HF) is a clinical syndrome characterized by impaired ability of the heart to fill or eject blood. Hypertension, idiopathic cardiomyopathy, diabetes, congenital cardiovascular defects, and valvular diseases may cause heart failure, but the most common causes are the coronary artery disease and myocardial infarction (MI). According to statistics, HF affects more than 5 million adult Americans, and this number is expected to increase to 8 million in 2030. The prognosis of HF is worrying, about 50% patients with HF are readmitted within 6 months of discharge, and half of them die within 5 years after diagnosis. The total estimated cost of HF in 2012 was approximately US$30.7 billion, and it is estimated that by 2030, the total cost of HF will reach US$69.7 billion. The molecular changes that occur during the development of HF include changes in protein kinase (PK) activity. Protein kinase A(PKA) has been shown to play a variety of important roles in cardiac function, including contraction, ion fluxes, metabolism, and gene transcription, etc.Changes in PKA activity may cause cardiomyopathy and HF, so PKA has become a potential target for HF drug development.
PKA is a serine/threonine kinase consisting of two regulatory subunits and two catalytic subunits. There are 4 isoforms of regulatory subunits (RIα, RIβ, RIIα, RIIβ), and 3 isoforms of catalytic subunits (Cα, Cβ, Cγ), each of which has different tissue expression and subcellular localization patterns. PKA is activated by cyclic adenosine monophosphate (cAMP) and is considered to be the most common downstream effector system for cAMP. In the absence of cAMP, PKA is a heterotetramer composed of two identical catalytic subunits (PKA-C) and two identical regulatory subunits (PKA-R). In the presence of cAMP, cAMP binds to the regulatory subunits, the catalytic subunits are released from the holoenzyme to phosphorylate the target substrate. This process involves the binding of extracellular ligands to G protein-coupled receptors, which regulate one of several isoforms of the adenylyl cyclase, leading to the production of cAMP.
Figure 1. Activation and inactivation mechanism of cAMP-dependent protein kinase A (PKA) (Saad, N.S. et al.2019)
Protein Kinase A (PKA) in Healthy and Failing Heart
PKA plays a variety of important roles in heart function. The phosphorylation of PKA in cardiomyocytes regulates many processes, including metabolism, gene transcription, ion fluxes, and contraction. Muscle cells usually break down glycogen to provide energy during a burst of activity. At the same time, PKA can phosphorylate glycogen synthase, causing it to inactivate and inhibit the conversion of glucose into glycogen. In addition, the cAMP-PKA pathway is activated by the binding of norepinephrine to the β-adrenergic receptor (βAR) in the heart, leading to the phosphorylation of multiple target proteins. PKA phosphorylates and activates cAMP regulatory element binding protein (CREB), thereby stimulating gene transcription.
Figure 2. Role of protein kinase A (PKA) in normal heart function (Saad, N.S. et al.2019)
In addition, PKA has a variety of substrates in cardiomyocytes, which can affect contractility in response to activated βAR signaling. PKA increases Ca2+ current, SR Ca2+ uptake and release, SR Ca2+ content, and the dissociation of Ca2+ from myofilaments. Since phospholamban (PLB) is phosphorylated by PKA, the PKA-PLB interaction is considered to be an important goal of drug development for the HF treatment. On the other hand, the activation of PKA has a synergistic effect on PKC-induced Raf-1 stimulation and mitogen-activated protein kinase in rat cardiomyocytes, and they play a non-negligible role in the development of cardiac hypertrophy. In addition, it was found that abnormalities in muscle-specific A-kinase anchoring protein (AKAP) may lead to cardiac hypertrophy. A large number of studies have shown that the activity and protein levels of PKA in HF are significantly increased compared with non-failure hearts. Increased PKA activity may lead to hyperphosphorylation of downstream targets, leading to loss of E-C coupling gain. Later studies reported that the prolonged activation of PKA can also lead to the hyperphosphorylation of PLB, however, this contradicts the above-mentioned reports of PLB hyperphosphorylation.
Figure 3. Role of activated Protein kinase A (PKA) in the excitation coupling mechanism and cardiac contraction and relaxation (Saad, N.S. et al.2019)
References
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Saad, N.S. et al. Protein Kinase A as a Promising Target for Heart Failure Drug Development. Archives of Medical Research. 2019.