SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation.

Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells. Proteomic analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performed in vitro EndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs.

Circular RNA circZFPM2 regulates cardiomyocyte hypertrophy and survival.

Hypertrophic cardiomyopathy (HCM) constitutes the most common genetic cardiac disorder. However, current pharmacotherapeutics are mainly symptomatic and only partially address underlying molecular mechanisms. Circular RNAs (circRNAs) are a recently discovered class of non-coding RNAs and emerged as specific and powerful regulators of cellular functions. By performing global circRNA-specific next generation sequencing in cardiac tissue of patients with hypertrophic cardiomyopathy compared to healthy donors, we identified circZFPM2 (hsa_circ_0003380). CircZFPM2, which derives from the ZFPM2 gene locus, is a highly conserved regulatory circRNA that is strongly induced in HCM tissue. In vitro loss-of-function experiments were performed in neonatal rat cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and HCM-patient-derived hiPSC-CMs. A knockdown of circZFPM2 was found to induce cardiomyocyte hypertrophy and compromise mitochondrial respiration, leading to an increased production of reactive oxygen species and apoptosis. In contrast, delivery of recombinant circZFPM2, packaged in lipid-nanoparticles or using AAV-based overexpression, rescued cardiomyocyte hypertrophic gene expression and promoted cell survival. Additionally, HCM-derived cardiac organoids exhibited improved contractility upon CM-specific overexpression of circZFPM2. Multi-Omics analysis further promoted our hypothesis, showing beneficial effects of circZFPM2 on cardiac contractility and mitochondrial function. Collectively, our data highlight that circZFPM2 serves as a promising target for the treatment of cardiac hypertrophy including HCM.

Tailored Yoga Intervention for Postlumbar Spine Surgical Pain Management: A Feasibility Study.

Introduction: Severe pain, anxiety, and high opioid use are common following lumbar spine surgery (LSS). Yoga helps to reduce pain and anxiety, but it has not been considered for postsurgical care. The authors developed and tested the feasibility of a tailored yoga program designed for individuals undergoing LSS and explored clinical feasibility of yoga intervention on measures of pain, function, psychological status, and opioid use. Methods: Individuals scheduled for LSS were randomized into yoga versus control groups presurgery. Participants in the yoga group received tailored yoga sessions plus usual care, whereas participants in the control group received usual care only during the hospital stay post-LSS. In-person daily yoga sessions were individually presented and performed in the participant's hospital room. Feasibility was assessed by recruitment and retention rates, rate of yoga session completion, tolerance to yoga intervention, and ability to carry out planned assessment. Exploratory clinical outcomes included pain, psychological measures, Timed-Up-and-Go test, gait distance, and opioid use, during the hospital stay post-LSS. Results: Forty-one participants were enrolled, of which 30 completed. There were no dropouts. Planned assessments were completed within 45 min, suggesting no excessive burden on participants. Baseline variables were similar across both groups. The majority of participants participated in yoga intervention on the day of surgery or one day after surgery with acceptance rate of 100%. Participants showed good tolerance to yoga intervention on 0-4 tolerance scale and by their reports of exploratory clinical outcomes. Conclusion: This study indicates feasibility for a modified yoga program for postoperative care following LSS due to participant tolerance and retention. The results provide preliminary framework for future confirmatory studies that can assess the potential benefits of yoga in reducing pain, catastrophizing behavior, and opioid use and improving function. A modified yoga program focusing on diaphragmatic breathing, relaxation, and core isometric contraction exercises can be an important adjunct intervention for patients undergoing LSS. CTR Number: This trial was registered in UMIN CTR (https://rctportal.niph.go.jp/en/) with registration number: UMIN000032595.

Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models.

In vitro modelling the complex (patho-) physiological conditions of the heart is a major challenge in cardiovascular research. In recent years, methods based on three-dimensional (3D) cultivation approaches have steadily evolved to overcome the major limitations of conventional adherent two-dimensional (2D) monolayer cultivation. These 3D approaches aim to study, reproduce or modify fundamental native features of the heart such as tissue organization and cardiovascular microenvironment. Therefore, these systems have great potential for (patient-specific) disease research, for the development of new drug screening platforms, and for the use in regenerative and replacement therapy applications. Consequently, continuous improvement and adaptation is required with respect to fundamental limitations such as cardiomyocyte maturation, scalability, heterogeneity, vascularization, and reproduction of native properties. In this review, 2D monolayer culturing and the 3D in vitro systems of cardiac spheroids, organoids, engineered cardiac microtissue and bioprinting as well as the ex vivo technique of myocardial slicing are introduced with their basic concepts, advantages, and limitations. Furthermore, recent advances of various new approaches aiming to extend as well as to optimize these in vitro and ex vivo systems are presented.