Increased serotonin (5HT) concentration and signaling, can lead to pathological remodeling of the cardiac valves. We previously showed that a reduction of the 5HT transporter (SERT) expression in the mitral valve (MV) contributes to the progression of degenerative MV regurgitation (MR). We sought to investigate the myocardial and valvular phenotype of SERT mice in order to identify remodeling mechanisms specific to the MV and left ventricular (LV) remodeling. Using 8- and 16-week-old WT and SERT mice we show that male and female animals deficient of SERT have pathological remodeling of the cardiac valves, myocardial fibrosis, diminished ejection fraction and altered left ventricular dimensions. In the MV and intervalvular area of the aortic valve (AV)-MV, gene expression, including Col1a1 mRNA, was progressively altered with age up until 16 weeks of age. In contrast, in the AV and myocardium, most gene expression changes occurred earlier and plateaued by 8 weeks. To explore basal differences in susceptibility to remodeling stimuli among cardiac valves, valve interstitial cells (VIC) were isolated from AV, MV, tricuspid valve (TV), pulmonary valve (PV) and fibroblasts (Fb) from the myocardial apex from 16 weeks old wild type (WT) mice. After 24h stimulation with 10 µM of 5HT, the gene expression of Col1a1 and Acta2 were upregulated in MVIC to a higher degree than in VIC from other valves and Fb. Treatment with TGFβ1 similarly upregulated Cola1 and Acta2 in MVIC and AVIC, while the increase was milder in right heart VIC and Fb. Experiments were also carried out with human VIC. In comparison to mice, human left heart VIC were more sensitive to 5HT and TGFβ1, upregulating COL1A1 and ACTA2; TGFβ1 upregulated HTR2B expression in all VIC. Our results support the hypothesis that a deleterious cardiac effect of SERT downregulation may be mediated by increased susceptibility to HTR2B-dependent pro-fibrotic mechanisms, which are distinct among VIC populations and cardiac fibroblasts, regardless of SERT activity. Given that HTR2B mechanisms involved in VIC and myocardial remodeling response are due to both 5HT and also to downstream related TGFβ1 and TNFα activity, targeting HTR2B could be a therapeutic strategy for dual treatment of MR and LV remodeling.
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http://dx.doi.org/10.1016/j.carpath.2024.107689 | DOI Listing |
Front Immunol
January 2025
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Introduction: Calcific aortic valve disease (CAVD) is increasingly prevalent among the aging population, and there is a notable lack of drug therapies. Consequently, identifying novel drug targets will be of utmost importance. Given that type 2 diabetes is an important risk factor for CAVD, we identified key genes associated with diabetes - related CAVD via various bioinformatics methods, which provide further potential molecular targets for CAVD with diabetes.
View Article and Find Full Text PDFACS Biomater Sci Eng
January 2025
College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, P.R. China.
Valvular heart disease (VHD) poses a significant threat to human health, and the transcatheter heart valve replacement (THVR) is the best treatment for severe VHD. Currently, the glutaraldehyde cross-linked commercial bioprosthetic heart valves (BHVs) remain the first choice for THVR. However, the cross-linking by glutaraldehyde exhibits several drawbacks, including calcification, inflammatory reactions, and difficult endothelialization, which limits the longevity and applicability of BHVs.
View Article and Find Full Text PDFAdv Mater
January 2025
Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
Direct ink writing is a 3D printing method that is compatible with a wide range of structural, elastomeric, electronic, and living materials, and it continues to expand its uses into physics, engineering, and biology laboratories. However, the large footprint, closed hardware and software ecosystems, and expense of commercial systems often hamper widespread adoption. This work introduces a compact, low-cost, multimaterial, and high-throughput direct ink writing 3D printer platform with detailed assembly files and instructions provided freely online.
View Article and Find Full Text PDFNat Commun
January 2025
Robotics Institute and State Key Laboratory of Mechanical System and Vibration, School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Hydrogel-based soft machines are promising in diverse applications, such as biomedical electronics and soft robotics. However, current fabrication techniques generally struggle to construct multimaterial three-dimensional hydrogel architectures for soft machines and robots, owing to the inherent hydrogel softness from the low-density polymer network nature. Herein, we present a multimaterial cryogenic printing (MCP) technique that can fabricate sophisticated soft hydrogel machines with accurate yet complex architectures and robust multimaterial interfaces.
View Article and Find Full Text PDFJ Mol Cell Cardiol
December 2024
Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. Electronic address:
Abnormal valve development is the most common congenital heart malformation. The transcription factor Sox7 plays a critical role in the development of vascular and cardiac septation. However, it remains unclear whether Sox7 is required for heart valve development.
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