This study demonstrates that Junctophilin-2 (JPH2) critically regulates cardiac fibroblast activation, extracellular matrix (ECM) generation, and angiogenesis after myocardial infarction by modulating Stim1 protein stability and SOCE function, providing a novel therapeutic target for cardiac repair mechanisms.
Literature Overview
This article, 'Junctophilin-2 Regulates Store-Operated Calcium Entry to Drive Cardiac Fibroblast Activation, Fibrotic Repair, and Angiogenesis Post-Myocardial Infarction', published in the journal Circulation, reviews and summarizes the regulatory role of Junctophilin-2 in cardiac fibroblast activation, fibrotic repair, and angiogenesis. The content is logically structured and information-rich, systematically elucidating its mechanisms and in vivo functions in cardiac repair.
Background Knowledge
Cardiac fibroblasts (CFs) play a central role in myocardial repair and fibrosis, with calcium signaling pathways—particularly SOCE (composed of Stim1 and Orai1/3)—serving as key regulators of fibroblast activation and differentiation. Junctophilin-2 (JPH2), a protein connecting the plasma membrane and endoplasmic reticulum, is known to regulate calcium homeostasis and excitation-contraction (E-C) coupling in cardiomyocytes, but its functional role in fibroblasts remains unclear. This study is the first to identify JPH2 as the exclusively expressed Junctophilin isoform in CFs, revealing its critical regulatory role in TGFβ-induced fibroblast activation, ECM secretion, and VEGF expression through in vitro and in vivo models. It further proposes a direct interaction between JPH2 and Stim1, offering a new target for cardiac repair and anti-fibrotic therapies.
Research Methods and Experiments
Human and mouse fibroblasts were cultured in vitro, combined with RT-qPCR, Western blotting, and immunofluorescence assays to confirm JPH2 as the dominant Junctophilin isoform in CFs. Ad-shJph2 or CF-specific Jph2 knockout mouse models were employed, integrating bioluminescence imaging, RNA-seq, and co-immunoprecipitation to demonstrate direct binding between JPH2 and Stim1 and its role in maintaining protein stability. In vivo cardiac repair, fibrosis, and angiogenesis post-MI were evaluated using Col1a2CreERT/Jph2flox/flox models, with fibroblast activation status assessed via Ki67, Postn, FN1, Col1a1, and other markers.
Key Conclusions and Perspectives
Research Significance and Prospects
This study unveils a previously unknown function of Junctophilin-2 in cardiac fibroblasts, establishing it as a potential therapeutic target for cardiac repair and anti-fibrotic interventions. Future research should explore JPH2's role in fibroblast subtypes, evaluate its therapeutic potential as a regulator of cardiac fibrosis or angiogenesis, and assess its applicability in humanized models.
Conclusion
In summary, this study reveals that Junctophilin-2 maintains Stim1 stability and SOCE functionality in cardiac fibroblasts to regulate TGFβ signaling, fibroblast activation, and angiogenesis. In myocardial infarction models, JPH2 deficiency reduces fibroblast activation, decreases VEGF expression, impairs scar formation, and promotes a hyper-proliferative state. These findings expand our understanding of Junctophilin family functions and establish JPH2 as a critical signaling hub in non-excitable cells. This discovery provides theoretical foundations for developing new strategies targeting cardiac repair and fibrosis, while suggesting potential directions for JPH2-related gene therapies or cellular interventions.
