Biochemical Structure and Function of TRAPP Complexes in the Cardiac System.

Trafficking protein particle (TRAPP) is well reported to play a role in the trafficking of protein products within the Golgi and endoplasmic reticulum. Dysfunction in TRAPP has been associated with disorders in the nervous and cardiovascular systems, but the majority of literature focuses on TRAPP function in the nervous system solely. Here, we highlight the known pathways of TRAPP and hypothesize potential impacts of TRAPP dysfunction on the cardiovascular system, particularly the role of TRAPP as a guanine-nucleotide exchange factor for Rab1 and Rab11. We also review the various cardiovascular phenotypes associated with changes in TRAPP complexes and their subunits.

Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (DspR451G/+). Mice homozygous for this variant displayed embryonic lethality. While DspR451G/+ mice were viable with reduced expression of DSP, no presentable arrhythmogenic or structural phenotypes were identified at baseline. However, increased afterload resulted in reduced cardiac performance, increased chamber dilation, and accelerated progression to heart failure. In addition, following catecholaminergic challenge, DspR451G/+ mice displayed frequent and prolonged arrhythmic events. Finally, aberrant localization of connexin-43 was noted in the DspR451G/+ mice at baseline, becoming more apparent following cardiac stress via pressure overload. In summary, cardiovascular stress is a key trigger for unmasking both electrical and structural phenotypes in one of the first humanized ACM mouse models.