CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy

Abstract

Increasing prevalence of diabetes mellitus worldwide has pushed the complex disease state to the foreground of biomedical research, especially concerning its multifaceted impacts on the cardiovascular system. Current therapies for diabetic cardiomyopathy have had a positive impact, but with diabetic patients still suffering from a significantly greater burden of cardiac pathology compared to the general population, the need for novel therapeutic approaches is great. A new therapeutic target, calcium/calmodulin-dependent kinase II (CaMKII), has emerged as a potential treatment option for preventing cardiac dysfunction in the setting of diabetes. Within the last 10 years, new evidence has emerged describing the pathophysiological consequences of CaMKII activation in the diabetic heart, the mechanisms that underlie persistent CaMKII activation, and the protective effects of CaMKII inhibition to prevent diabetic cardiomyopathy. This review will examine recent evidence tying cardiac dysfunction in diabetes to CaMKII activation. It will then discuss the current understanding of the mechanisms by which CaMKII activity is enhanced during diabetes. Finally, it will examine the benefits of CaMKII inhibition to treat diabetic cardiomyopathy, including contractile dysfunction, heart failure with preserved ejection fraction, and arrhythmogenesis. We intend this review to serve as a critical examination of CaMKII inhibition as a therapeutic strategy, including potential drawbacks of this approach.

Identification of Bioactive Peptides from Nannochloropsis oculata Using a Combination of Enzymatic Treatment, in Silico Analysis and Chemical Synthesis

“…Fractions of these peptides generated following in silico gastrointestinal digestion Table 2 ) also predict that identified peptides could have antioxidant and Calcium/calmodulin-dependent protein kinases (CaMKs) inhibitory activities (CAMKII inhibitors). CAMKII inhibitors are key regulators of calcium signaling in health and disease and CaMKII inhibition displays cardioprotection [ 40 ].…”

Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression

“…In recent years, CAMK2 has garnered a great deal of attention for its pivotal role in the arrhythmias of chronic illness ( 59 ). The isoform-specific inhibitor of CAMK2D (the main cardiac isoform of CAMK2) could be used to target the cardiac-specific pathology of autonomously activated CAMK2 in diabetes ( 60 ), while avoiding off-target effects in other tissues, such as α and β isoforms of CAMK2, and disruption of memory formation in the hippocampus ( 61 ). A recent clinical trial revealed that the CAMK2 inhibitor appears to be well accepted and safe among patients ( 62 ), suggesting that it should pave the way for future development of CAMK2 inhibitors in other conditions, such as the treatment of MDR cancer patients.…”

Differential changes in cyclic adenosine 3′‐5′ monophosphate (cAMP) effectors and major Ca2+ handling proteins during diabetic cardiomyopathy

“…33,53 CaMKII, a critical transducer of Ca 2+ signalling, is a multifunctional protein kinase that phosphorylates a wide range of substrates and regulates numerous cellular functions, including ECC. 35,54 CaMKII has been proposed as a key contributor to the deleterious effects of chronic β-AR activation in DCM, primarily by exacerbating RyR2-mediated diastolic Ca 2+ leak. 55,56 Therefore, we determined whether the expression of CaMKII is altered in the diabetic myocardium during the progression of DCM.…”

“…32,33 Moreover, there is little information concerning Epac modification in DCM despite its established role in mediating pro-hypertrophic effects of β-AR stimulation. 34 Although disturbances in Ca 2+ signalling and CaMKII have been investigated in DCM, 30,35,36 data on actual changes affecting the expression and activity of the proteins involved in Ca 2+ homeostasis during the evolution of DCM are controversial. 30,31,33 In a recent study, we characterized the evolution of cardiac structure and function in a rat model of DCM at 4, 8 and 12 weeks after streptozotocin (STZ)-induced type 1 diabetes (T1D).…”