Protein Kinase A as a Promising Target for Heart Failure Drug Development

Abstract

Heart failure (HF) is a clinical syndrome characterized by impaired ability of the heart to fill or eject blood. HF is rather prevalent and it represents the foremost reason of hospitalization in the United States. The costs linked to HF overrun those of all other causes of disabilities, and death in the United States and all over the developed as well as the developing countries which amplify the supreme significance of its prevention. Protein kinase (PK) A plays multiple roles in heart functions including, contraction, metabolism, ion fluxes, and gene transcription. Altered PKA activity is likely to cause the progression to cardiomyopathy and HF. Thus, this review is intended to focus on the roles of PKA and PKA-mediated signal transduction in the healthy heart as well as during the development of HF. Furthermore, the impact of cardiac PKA inhibition/activation will be highlighted to identify PKA as a potential target for the HF drug development.

Depressed β‐adrenergic inotropic responsiveness and intracellular calcium handling abnormalities in Duchenne Muscular Dystrophy patients’ induced pluripotent stem cell–derived cardiomyocytes

“…The next step downstream to ADRβ1 is activation of adenylyl cyclase (AC) via Gs, resulting in increased cAMP levels. The primary target of cAMP is protein kinase A (PKA) which phosphorylates several key proteins essential for cardiac function, such as the L‐type calcium channel, phospholamban, troponin I and RyR 46 . Therefore, because ADRβ1 is down‐regulated, its stimulation will result in attenuated AC activation, decreased cAMP levels, and consequently blunted positive inotropic response to isoproterenol.…”

Phenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapy

“…We conducted comprehensive studies of the lamp2 e2/e2 fish using the newly developed phenotyping tools [32,36] and noted reduced cardiac pump function and blunted lusitropic β-adrenergic myocardium response. Blunted β-adrenergic response is a common feature of the failing human hearts, which could be due to uncoupling between myofilament Ca 2+ sensitivity and N-terminal phosphorylation of the cardiac isoform of Troponin I by protein kinase A [43,44]. It remains to be investigated whether phosphorylation of thin myofilaments is affected in lamp2 KO upon β-adrenergic stimulation or treatment with protein kinase A in mammalian models.…”

Oxidation of Protein Kinase A Regulatory Subunit PKARIα Protects Against Myocardial Ischemia-Reperfusion Injury by Inhibiting Lysosomal-Triggered Calcium Release

“…Under physiological conditions, PKA contributes to the cardiac response to catecholamine stimulation through catalyzed phosphorylation of proteins involved in excitation-contraction coupling, metabolism, and cardiomyocyte hypertrophy. 12 , 13 In disease states, however, persistent activation of PKA signaling, or altered expression of PKA isotypes, has been linked to maladaptive remodeling, pathological hypertrophy, and the progression to heart failure, 14 making pharmacological targeting of PKA an attractive therapy for the treatment of cardiac disease.…”