Junctophilin-2 Regulates Store-Operated Calcium Entry to Drive Cardiac Fibroblast Activation, Fibrotic Repair, and...

Area of Science:

• Cardiovascular Biology
• Cellular Signaling
• Fibroblast Biology

Background:

• Cardiac fibroblasts (CFs) regulate myocardial repair and remodeling post-injury through calcium (Ca2+) homeostasis.
• Junctophilin-2 (JPH2) is a known regulator of Ca2+ signaling in cardiomyocytes, but its role in CFs is unknown.

Purpose of the Study:

• To investigate the expression and function of Junctophilin-2 (Jph2) in cardiac fibroblasts (CFs).
• To elucidate the role of Jph2 in CF calcium handling, activation, and response to cardiac injury.

Main Methods:

• Assayed Jph2 expression in human and mouse CFs via qPCR, Western blotting, and immunofluorescence.
• Utilized live-cell Ca2+ imaging, RNA sequencing, and TGFβ stimulation in Jph2-deficient CFs.
• Employed fibroblast-specific Jph2 knockout mice (Jph2 fKO) to assess in vivo cardiac function, remodeling, and angiogenesis post-myocardial infarction.

Main Results:

• Jph2 is the sole junctophilin in CFs, upregulated post-myocardial infarction.
• Jph2 deficiency in CFs impaired activation, reduced extracellular matrix production, and diminished VEGF expression after TGFβ treatment.
• Jph2 knockout mice showed exacerbated cardiac remodeling, systolic dysfunction, impaired angiogenesis, and altered CF proliferation post-myocardial infarction.
• Jph2 interacts with Stim1, regulating store-operated Ca2+ entry and TGFβ signaling pathways.

Conclusions:

• Jph2 is essential for CF calcium homeostasis, activation, and extracellular matrix production.
• Jph2 promotes angiogenesis in the infarcted heart.
• Jph2 acts as a central regulator of cardiac repair after myocardial injury.