Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

Abstract

Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socioeconomic burden. Calcium (Ca 2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca 2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca 2+ cycling and signaling play a vital role in maintaining Ca 2+ homeostasis. Changes to the expression levels and function of Ca 2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca 2+ homeostasis in CVD. The remodeling of Ca 2+-handling proteins therefore results in impaired Ca 2+ cycling, Ca 2+ leak from the sarcoplasmic reticulum and reduced Ca 2+ clearance, all of which contributes to increased intracellular Ca 2+. Currently, approved treatments for targeting Ca 2+ handling dysfunction in CVD are focused on Ca 2+ channel blockers. However, whilst Ca 2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca 2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca 2+handling and-signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

DBA/1 mice display equivalent cardiac function to C57BL/6J mice

“…The contraction and relaxation of cardiac myocytes depends on the cascade of calcium release and uptake by sarcoplasmic reticulum (SR) and the movement of myofilaments (Njegic et al., 2020). PLB negatively controls the sarco/endoplasmic reticulum Ca 2+ ‐ATPase, which is the calcium pump for taking calcium into the SR and triggers the relaxation of the heart.…”

Linked biaromatic compounds as cardioprotective agents

“…Inactivation of T‐type Ca 2+ channels results in bradycardia and delayed AV conduction, highlighting the importance of the channel in cardiac rhythm. [ 181–183 ]…”

“…T-type Ca 2+ channels are localized in the pacemaker regions of the heart (the SAN, AVN, and Purkinje fibers) where they are thought to contribute to SAN pacemaker activity and AV conduction. Inactivation of T-type Ca 2+ channels results in bradycardia and delayedAV conduction, highlighting the importance of the channel in cardiac rhythm [181][182][183]. 2.4.1 | L-type Ca 2+ channel blockersVerapamil and its family As already indicated above, the first representative of the calcium channel blockers family was verapamil discovered at Knoll AG (Germany) during the synthesis of papaverine derivatives in the late 1950s to early 1960s.…”

New Therapeutic Agents in Obesity-Related Cardiovascular Disorders: Molecular and Cellular Insights

“…These findings are also indicating the contribution of co-factors in the development of obesity as well as the importance of controlling obesityrelated comorbidities into our healthy life. Supporting these statement, considering the close association with altered Ca 2+ -homeostasis and cardiac arrhythmias, a recent article addressed the molecular changes of some proteins associated with both Ca 2+handling and Ca 2+ -signaling together with their potential as novel therapeutic targets for obesity [83].…”