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Calcium Regulation on the Atrial Regional Difference of Collagen Production Activity in Atrial Fibrogenesis
Cheng-Chih Chung1,2,3, Yung-Kuo Lin1,2,3, Yao-Chang Chen4
1Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Insights
Left atrium fibroblasts show higher calcium influx and collagen production than right atrium fibroblasts, driven by calcium signaling differences. Inhibiting calcium signaling reduces this fibrotic potential.
Area of Science:
- Cardiology
- Cell Biology
- Biochemistry
Background:
- Atrial fibrosis is a key factor in heart failure and atrial fibrillation.
- Left atrium (LA) fibroblasts display greater fibrosis than right atrium (RA) fibroblasts, but the underlying mechanisms are unclear.
- Calcium (Ca²⁺) signaling influences fibroblast pro-fibrotic activities.
Purpose of the Study:
- To investigate if differences in Ca²⁺ homeostasis contribute to the distinct fibrotic potential of LA and RA fibroblasts.
- To compare Ca²⁺ signaling pathways and collagen production in LA versus RA fibroblasts.
Main Methods:
- Isolated rat LA and RA fibroblasts were analyzed using Ca²⁺ imaging, patch clamp assays, and Western blotting.
- Protein expression levels of collagen, phosphorylated CaMKII, PLC, STIM1, and TRPC3 were quantified.
- The effects of Ca²⁺ chelation (EGTA) and CaMKII inhibition (KN93) on fibroblast activity were assessed.
Main Results:
- LA fibroblasts demonstrated increased Ca²⁺ entry and gadolinium-sensitive currents compared to RA fibroblasts.
- LA fibroblasts showed higher expression of pro-collagen type I, type III, phosphorylated CaMKII, PLC, STIM1, and TRPC3.
- EGTA treatment and KN93 inhibition normalized collagen and phosphorylated CaMKII expression in LA fibroblasts, indicating Ca²⁺ and CaMKII dependence.
Conclusions:
- Differential phosphorylated PLC signaling and gadolinium-sensitive Ca²⁺ channels in LA and RA fibroblasts lead to varied Ca²⁺ influx.
- This Ca²⁺ influx influences phosphorylated CaMKII expression and subsequent collagen production, explaining the fibrotic differences.
- Targeting Ca²⁺ signaling pathways may offer therapeutic strategies for atrial fibrosis.
Background:
Atrial fibrosis plays an important role in the genesis of heart failure and atrial fibrillation. The left atrium (LA) exhibits a higher level of fibrosis than the right atrium (RA) in heart failure and atrial arrhythmia. However, the mechanism for the high fibrogenic potential of the LA fibroblasts remains unclear. Calcium (Ca2+) signaling contributes to the pro-fibrotic activities of fibroblasts. This study investigated whether differences in Ca2+ homeostasis contribute to differential fibrogenesis in LA and RA fibroblasts.
Methods:
Ca2+ imaging, a patch clamp assay and Western blotting were performed in isolated rat LA and RA fibroblasts.
Results:
The LA fibroblasts exhibited a higher Ca2+ entry and gadolinium-sensitive current compared with the RA fibroblasts. The LA fibroblasts exhibited greater pro-collagen type I, type III, phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII), phosphorylated phospholipase C (PLC), stromal interaction molecule 1 (STIM1) and transient receptor potential canonical (TRPC) 3 protein expression compared with RA fibroblasts. In the presence of 1 mmol/L ethylene glycol tetra-acetic acid (EGTA, Ca2+ chelator), the LA fibroblasts had similar pro-collagen type I, type III and phosphorylated CaMKII expression compared with RA fibroblasts. Moreover, in the presence of KN93 (a CaMKII inhibitor, 10 μmol/L), the LA fibroblasts had similar pro-collagen type I and type III compared with RA fibroblasts.
Conclusion:
The discrepancy of phosphorylated PLC signaling and gadolinium-sensitive Ca2+ channels in LA and RA fibroblasts induces different levels of Ca2+ influx, phosphorylated CaMKII expression and collagen production.
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