Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk

Abstract

Calcium homeostasis in the cardiomyocyte is critical to the regulation of normal cardiac function. Abnormal calcium dynamics such as altered uptake by the sarcoplasmic reticulum (SR) Ca2+-ATPase and increased diastolic SR calcium leak are involved in the development of maladaptive cardiac remodeling under pathological conditions. Ca2+/calmodulin-dependent protein kinase II-δ (CaMKIIδ) is a well-recognized key molecule in calcium dysregulation in cardiomyocytes. Elevated cellular stress is known as a common feature during pathological remodeling, and c-jun N-terminal kinase (JNK) is an important stress kinase that is activated in response to intrinsic and extrinsic stress stimuli. Our lab recently identified specific actions of JNK isoform 2 (JNK2) in CaMKIIδ expression, activation, and CaMKIIδ-dependent SR Ca2+ mishandling in the stressed heart. This review focuses on the current understanding of cardiac SR calcium handling under physiological and pathological conditions as well as the newly identified contribution of the stress kinase JNK2 in CaMKIIδ-dependent SR Ca2+ abnormal mishandling. The new findings identifying dual roles of JNK2 in CaMKIIδ expression and activation are also discussed in this review.

Inter-Individual Variation and Cardioprotection in Anthracycline-Induced Heart Failure

“…Secondly, dysregulation of calcium homeostasis has been observed in multiple pathological conditions including cardiac remodelling and heart failure [ 75 , 76 , 77 , 78 ] and tumorigenesis [ 79 ]. Specifically, transient receptor potential channels (including TRPC6) which are key regulators of intracellular calcium homeostasis are also involved in the main processes of metastasis such as migration, invasion, and tumor vascularization [ 80 ].…”

A special issue on calcium dynamics of the heart: remodeling of ion channels and regulatory pathways

“…In this Special Issue, several articles (Blatter et al, Lahiri et al, McKee et al, Hamilton et al, Wang et al, Xie et al, Rosenberg et al, Fill et al) [2,7,8,12,13,[17][18][19] have thoroughly reviewed the physiological role of the excitation-contraction coupling (ECC) in the cardiomyocyte and a well-established concept that defective intracellular Ca 2+ cycling acts as a key contributing factor to an elevated predisposition for arrhythmias and/or impaired cardiac contractility in pathologically altered hearts. Under certain conditions such as exercise, aging, excessive alcohol exposure, obesity, diabetes, inherited mutational burdens, ischemia, systemic inflammation, these extrinsic/intrinsic stress stimuli trigger adaptive remodeling of Ca 2+ handling machinery and regulatory signaling pathways in cardiac cells that are necessary to deliver an adequate acute response but also ensures long-term survival.…”

“…In addition, disrupted intracellular Ca 2+ cycling and SR Ca 2+ mishandling critically contribute to the development of fatal ventricular fibrillation (a major cause of sudden cardiac death) and atrial fibrillation (the most common arrhythmia, with a higher mortality due to significantly increased risk for stroke and heart failure). [8,12,13,17,18] were also included regarding the new findings of regulatory mechanisms of stress stimuli (i.e., aging, excessive alcohol abuse, inflammation, ischemic-reperfusion) or inherited gene mutations (i.e., Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Long QT Syndrome (LQTS)) in disrupted SR Ca 2+ dynamics via altered channel function of RyR2, IP 3 R2, and STIM1-Orai1, which lead to changed SR Ca 2+ load and significantly increased diastolic SR Ca 2+ leak promoting the initiation or progression of arrhythmias and heart failure. Altered enzyme activity and/or changed interactions between kinases/protein phosphatases and ion channels critically contribute to these stress-evoked changes in the Ca 2+ homeostasis and cardiac electrical and mechanical dysfunction.…”