No abstract

JNK activation contributes to Cx43 reductions that promote development of AF. Modulation of JNK may be a potential novel therapeutic approach to prevent and treat AF.

SARS-CoV-2 vaccines based on inactivated live virus, recombinant viral vector, mRNA, DNA, and recombinant protein are currently in clinical trials. [6] Among these agents, an mRNA-based vaccine candidate quickly entered the clinical trial, because of the fast process for developing and manufacturing mRNA. [7] In order to express an antigen effectively, an mRNA requires several essential components, including 5′ cap, 5′ untranslated region (5′ UTR), antigen-encoding sequence, 3′ untranslated region (3′ UTR), and the poly adenylated tail. [8] Among these components, the 5′ UTR and 3′ UTR are unique regulators for protein translation. [9] The design and selection of 5′ UTR and 3′ UTR are critically important to ensure the sufficient production of antigens and efficacious vaccination. [10]

Messenger RNA (mRNA) therapeutics have been explored to treat various genetic disorders. Lipid-derived nanomaterials are currently one of the most promising biomaterials that mediate effective mRNA delivery. However, efficiency and safety of this nanomaterial-based mRNA delivery remains a challenge for clinical applications. Here, we constructed a series of lipid-like nanomaterials (LLNs), named functionalized TT derivatives (FTT), for mRNA-based therapeutic applications in vivo. After screenings on the materials, we identified FTT5 as a lead material for efficient delivery of long mRNAs, such as human factor VIII (hFVIII) mRNA (~4.5 kb) for expression of hFVIII protein in hemophilia A mice. Moreover, FTT5 LLNs demonstrated high percentage of base editing on PCSK9 in vivo at a low dose of base editor mRNA (~5.5 kb) and single guide RNA. Consequently, FTT nanomaterials merit further development for mRNA-based therapy.

BACKGROUND Excessive binge alcohol drinking has acute cardiac arrhythmogenic effects, including promotion of atrial fibrillation (AF), which underlies “Holiday Heart Syndrome.” The mechanism that couples binge alcohol abuse with AF susceptibility remains unclear. We previously reported stress-activated c-Jun N-terminal kinase (JNK) signaling contributes to AF development. This is interesting because JNK is implicated in alcohol-caused organ malfunction beyond the heart. OBJECTIVES The purpose of this study was to detail how JNK promotes binge alcohol-evoked susceptibility to AF. METHODS The authors found binge alcohol-exposure leads to activated JNK, specifically JNK2. Furthermore, binge alcohol induces AF (24- vs. 1.8-Hz burst pacing-induced episodes per attempt per animal), higher incidence of diastolic intracellular Ca 2+ activity (Ca 2+ waves, sarcoplasmic reticulum [SR] Ca 2+ leakage), and membrane voltage (V m ) and systolic Ca 2+ release spatiotemporal heterogeneity (Δt Vm-Ca ). These changes were completely eliminated by JNK inhibition both in vivo and in vitro. calmodulin kinase II (CaMKII) is a proarrhythmic molecule known to drive SR Ca 2+ mishandling. RESULTS The authors report for the first time that binge alcohol activates JNK2, which subsequently phosphorylates the CaMKII protein, enhancing CaMKII-driven SR Ca 2+ mishandling. CaMKII inhibition eliminates binge alcohol-evoked arrhythmic activities. CONCLUSIONS Our studies demonstrate that binge alcohol exposure activates JNK2 in atria, which then drives CaMKII activation, prompting aberrant Ca 2+ waves and, thus, enhanced susceptibility to atrial arrhythmia. Our results reveal a previously unrecognized form of alcohol-driven kinase-on-kinase proarrhythmic crosstalk. Atrial JNK2 function represents a potential novel therapeutic target to treat and/or prevent AF.