Challenges and Opportunities for Therapeutic Targeting of Calmodulin Kinase II in Heart

Abstract

Heart failure remains a major health burden around the world. Despite great progress in delineation of molecular mechanisms underlying development of disease, standard therapy has not advanced at the same pace. The multifunctional signaling molecule Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) has received considerable attention over recent years for its central role in maladaptive remodeling and arrhythmias in the setting of chronic disease. However, these basic science discoveries have yet to translate into new therapies for human patients. This review addresses both the promise and barriers to developing translational therapies that target CaMKII signaling to abrogate pathologic remodeling in the setting of chronic disease. Efforts in small molecule design are discussed, as well as alternative targeting approaches that exploit novel avenues for compound delivery and/or genetic approaches to affect cardiac CaMKII signaling. These alternative strategies provide hope for overcoming some of the challenges that have limited the development of new therapies.

CaMKIIδ Splice Variants in the Healthy and Diseased Heart

“…Overall, CaMKIIδ-directed therapeutics show great promise for three main reasons: (1) its levels are upregulated in both experimental models of heart failure and human samples which suggests a causal role for increased CaMKIIδ activation in disease, (2) the transgenic overexpression of CaMKIIδA, -δC and -δ9 leads to adverse cardiac remodeling accompanied by contractile dysfunction, and most importantly (3) CaMKIIδ inhibition is generally associated with protection against cardiac dysfunction and a reduction in cardiac damage in animal models subjected to detrimental stimuli. Nevertheless, the importance of CaMKIIδ in physiological processes, as well as the proposed protective effects of, e.g., CaMKIIδB suggest that CaMKIIδ-directed therapeutics require high specificity [For further details see ( Nassal et al, 2020 )].…”

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

“…Molecular structure and function of CaMKII. CaMKII is a serine/threonine kinase that is composed of two stacked hexamers assembled from 12 monomers (22,23). Each monomer is composed of an N-terminal catalytic region, an intermediate regulatory do-main and a C-terminal associated region (15,23).…”

“…CaMKII is a serine/threonine kinase that is composed of two stacked hexamers assembled from 12 monomers (22,23). Each monomer is composed of an N-terminal catalytic region, an intermediate regulatory do-main and a C-terminal associated region (15,23). The catalytic region contains an ATP and target substrate binding site, which is responsible for the regulation of kinase activity (23).…”

“…Each monomer is composed of an N-terminal catalytic region, an intermediate regulatory do-main and a C-terminal associated region (15,23). The catalytic region contains an ATP and target substrate binding site, which is responsible for the regulation of kinase activity (23). Under basic conditions, the function of the catalytic region is inhibited by interacting with the intermediate regulatory region (23).…”

LncRNAs in cardiac hypertrophy: From basic science to clinical application

“…Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) is associated with phosphorylation of a number of Ca 2+ handling proteins with α, β, γ, δ isoforms, relating to the activation of the SERCA2a and RyR2, the disturbing of which would lead inappropriate membrane potential depolarizations, and the higher activity of CaMKII would cause cardiomyocyte hypertrophy 42‐45 . Lnc‐TINCR could regulation the expression of CaMKII via epigenetically silencing, as knockdown of lnc‐TINCR was found to reduce EZH2 occupancy and H3K27me3 binding in the promoter of CaMKII in cardiomyocytes (Figure 2).…”