Novel Identification of Ankyrin-R in Cardiac Fibroblasts and a Potential Role in Heart Failure.

Altered ankyrin-R (AnkR; encoded by ANK1) expression is associated with diastolic function, left ventricular remodeling, and heart failure with preserved ejection fraction (HFpEF). First identified in erythrocytes, the role of AnkR in other tissues, particularly the heart, is less studied. Here, we identified the expression of both canonical and small isoforms of AnkR in the mouse myocardium. We demonstrate that cardiac myocytes primarily express small AnkR (sAnkR), whereas cardiac fibroblasts predominantly express canonical AnkR. As canonical AnkR expression in cardiac fibroblasts is unstudied, we focused on expression and localization in these cells. AnkR is expressed in both the perinuclear and cytoplasmic regions of fibroblasts with considerable overlap with the trans-Golgi network protein 38, TGN38, suggesting a potential role in trafficking. To study the role of AnkR in fibroblasts, we generated mice lacking AnkR in activated fibroblasts (Ank1-ifKO mice). Notably, Ank1-ifKO mice fibroblasts displayed reduced collagen compaction, supportive of a novel role of AnkR in normal fibroblast function. At the whole animal level, in response to a heart failure model, Ank1-ifKO mice displayed an increase in fibrosis and T-wave inversion compared with littermate controls, while preserving cardiac ejection fraction. Collagen type I fibers were decreased in the Ank1-ifKO mice, suggesting a novel function of AnkR in the maturation of collagen fibers. In summary, our findings illustrate the novel expression of AnkR in cardiac fibroblasts and a potential role in cardiac function in response to stress.

Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

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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.

Toward living neuroprosthetics: developing a biological brain pacemaker as a living neuromodulatory implant for improving parkinsonian symptoms.

Objective.Therapeutic intervention for Parkinson's disease (PD) via deep brain stimulation (DBS) represents the current paradigm for managing the advanced stages of the disease in patients when treatment with pharmaceuticals becomes inadequate. Although DBS is the prevailing therapy in these cases, the overall effectiveness and reliability of DBS can be diminished over time due to hardware complications and biocompatibility issues with the electronic implants. To achieve a lifetime solution, we envision that the next generation of neural implants will be entirely 'biological' and 'autologous', both physically and functionally. Thus, in this study, we set forth toward developing a biological brain pacemaker for treating PD. Our focus is to investigate engineering strategies for creating a multicellular biological circuit that integrates innate biological design and function while incorporating principles of neuromodulation to create a biological mechanism for delivering high-frequency stimulation with cellular specificity.Approach.We engineer a 3D multicellular circuit design built entirely from biological and biocompatible components using established tissue engineering protocols to demonstrate the feasibility of creating a living neural implant. Furthermore, using 2D co-culture systems, we investigate the physiologically relevant parameters that would be necessary to further develop a therapeutic benefit of high-frequency stimulation with cellular specificity within our construct design.Main results.Our results demonstrate the feasibility of fabricating a 3D multicellular circuit device in an implantable form. Furthermore, we show we can organize cellular materials to create potential functional connections in normal physiological conditions, thus laying down the foundation of designing a high-frequency pacing system for selective and controlled therapeutic neurostimulation.Significance.The findings from this study may lead to the future development of autologous living neural implants that both circumvent the issues inherent in electronic neural implants and form more biocompatible devices with lifelong robustness to repair and restore motor functions, with the ultimate benefit for patients with PD.