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RationaleWe recently discovered pivotal contributions of stress kinase JNK2 (c-Jun N-terminal kinase isoform 2) in increased risk of atrial fibrillation through enhanced diastolic sarcoplasmic reticulum (SR) calcium (Ca2+) leak via RyR2 (ryanodine receptor isoform 2). However, the role of JNK2 in the function of the SERCA2 (SR Ca2+-ATPase), essential in maintaining SR Ca2+ content cycling during each heartbeat, is completely unknown.ObjectiveTo test the hypothesis that JNK2 increases SERCA2 activity SR Ca2+ content and exacerbates an arrhythmic SR Ca2+ content leak-load relationship.Methods and resultsWe used confocal Ca2+ imaging in myocytes and HEK-RyR2 (ryanodine receptor isoform 2-expressing human embryonic kidney 293 cells) cells, biochemistry, dual Ca2+/voltage optical mapping in intact hearts from alcohol-exposed or aged mice (where JNK2 is activated). We found that JNK2, but not JNK1 (c-Jun N-terminal kinase isoform 1), increased SERCA2 uptake and consequently elevated SR Ca2+ content load. JNK2 also associates with and phosphorylates SERCA2 proteins. JNK2 causally enhances SERCA2-ATPase activity via increased maximal rate, without altering Ca2+ affinity. Unlike the CaMKII (Ca2+/calmodulin-dependent kinase II)-dependent JNK2 action in SR Ca2+ leak, JNK2-driven SERCA2 function was CaMKII independent (not prevented by CaMKII inhibition). With CaMKII blocked, the JNK2-driven SR Ca2+ loading alone did not significantly raise leak. However, with JNK2-CaMKII-driven SR Ca2+ leak present, the JNK2-enhanced SR Ca2+ uptake limited leak-induced reduction in SR Ca2+, normalizing Ca2+ transient amplitude, but at a higher arrhythmogenic SR Ca2+ leak. JNK2-specific inhibition completely normalized SR Ca2+ handling, attenuated arrhythmic Ca2+ activities, and alleviated atrial fibrillation susceptibility in aged and alcohol-exposed myocytes and intact hearts.ConclusionsWe have identified a novel JNK2-induced activation of SERCA2. The dual action of JNK2 in CaMKII-dependent arrhythmic SR Ca2+ leak and a CaMKII-independent uptake exacerbates atrial arrhythmogenicity, while helping to maintain normal levels of Ca2+ transients and heart function. JNK2 modulation may be a novel therapeutic target for atrial fibrillation prevention and treatment.

RationaleAtrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable.ObjectiveTo explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca2+ handling and consequently Ca2+-mediated atrial arrhythmias.Methods and resultsWe used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca2+/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca2+ release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca2+ leak mediated by RyR2 channels. This leads to aberrant intracellular Ca2+ waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition.ConclusionsWe have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.

Premise: Stem xylem transports water and nutrients, mechanically supports aboveground tissues, and stores water and nonstructural carbohydrates. These three functions are associated with three types of cells—vessel, fiber, and parenchyma, respectively. Methods: We measured stem theoretical hydraulic conductivity (Kt), modulus of elasticity (MOE), tissue water content, starch, soluble sugars, cellulose, and xylem anatomical traits in 15 liana and 16 tree species across three contrasting sites in Southwest China. Results: Lianas had higher hydraulic efficiency and tissue water content, but lower MOE and cellulose than trees. Storage traits (starch and soluble sugars) did not significantly differ between lianas and trees, and trait variation was explained mainly by site, highlighting how environment shapes plant storage strategies. Kt was significantly positively correlated with vessel diameter and vessel area fraction in lianas and all species combined. The MOE was significantly positively correlated with fiber area fraction, wood density, and cellulose in lianas and across all species. The tissue water content was significantly associated with parenchyma area fraction in lianas. Support function was strongly linked with transport and storage functions in lianas. In trees, transport and support functions were not correlated, while storage function was tightly linked with transport and support functions. Conclusions: These findings enhance our understanding of the relationship between stem xylem structure and function in lianas and trees, providing valuable insights into how plants adapt to environmental changes and the distinct ecological strategies employed by lianas and by trees to balance the demands of hydraulic transport, mechanical support, and storage. [ABSTRACT FROM AUTHOR]

Long-term alcohol consumption leads to cardiac arrhythmias including atrial fibrillation (AF), the most common alcohol-related arrhythmia. While AF significantly increases morbidity and mortality in patients, it takes years for an alcoholic individual undergoing an adaptive status with normal cardiac function to reach alcoholic cardiomyopathy. The underlying mechanism remains unclear to date. In this study, we assessed the functional role of JNK2 in long-term alcohol-evoked atrial arrhythmogenicity but preserved cardiac function. Wild-type (WT) mice and cardiac-specific JNK2dn mice (with an overexpression of inactive dominant negative (dn) JNK2) were treated with alcohol (2 g/kg daily for 2 months; 2 Mo). Confocal Ca2+ imaging in the intact mouse hearts showed that long-term alcohol prolonged intracellular Ca2+ transient decay, and increased pacing-induced Ca2+ waves, compared to that of sham controls, while cardiac-specific JNK2 inhibition in JNK2dn mice precluded alcohol-evoked Ca2+-triggered activities. Moreover, activated JNK2 enhances diastolic SR Ca2+ leak in 24 h and 48 h alcohol-exposed HL-1 atrial myocytes as well as HEK-RyR2 cells (inducible expression of human RyR2) with the overexpression of tGFP-tagged active JNK2-tGFP or inactive JNK2dn-tGFP. Meanwhile, the SR Ca2+ load and systolic Ca2+ transient amplitude were both increased in ventricular myocytes, along with the preserved cardiac function in 2 Mo alcohol-exposed mice. Moreover, the role of activated JNK2 in SR Ca2+ overload and enhanced transient amplitude was also confirmed in long-term alcohol-exposed HL-1 atrial myocytes. In conclusion, our findings suggest that long-term alcohol-activated JNK2 is a key driver in preserved cardiac function, but at the expense of enhanced cardiac arrhythmogenicity. Modulating JNK2 activity could be a novel anti-arrhythmia therapeutic strategy. [ABSTRACT FROM AUTHOR]