Calcium Regulation on the Atrial Regional Difference of Collagen Production Activity in Atrial Fibrogenesis

Abstract

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.

Regional Diversities in Fibrogenesis Weighed as a Key Determinant for Atrial Arrhythmogenesis

“…This finding suggests that part of the RA fibroblasts may come from different embryonic germ layers to those of LA fibroblasts. In addition, the dissimilar characteristics between LA and RA fibroblasts are correlated with the diversity in oxidative stress, nitric oxide (NO) signaling, TGF-β production, and Ca 2+ signaling [ 36 , 59 , 60 ]. Table 1 summarizes the potential targets underlying different fibrogenesis between the RA and LA.…”

“…Extracellular Ca 2+ entry and endoplasmic reticulum (ER) Ca 2+ release contribute to the increase in intracellular Ca 2+ . In our previous study, we found that, compared with RA fibroblasts, LA fibroblasts exhibited higher Ca 2+ entry, thereby inducing greater collagen production ( Figure 2 ) [ 59 ]. In addition, compared with RA tissue, LA tissue exhibited greater chymase production, which is a profibrotic protease that can induce Ca 2+ influx [ 85 , 105 , 106 ].…”

“…Moreover, compared to LA tissue, RA tissue exhibits higher estrogen receptor-α expression, which is constitutionally expressed on cardiac fibroblasts and may inhibit the profibrotic cellular activities of cardiac fibroblasts through the modulation of Ca 2+ homeostasis [ 64 , 67 , 68 , 108 , 109 , 110 ]. In our previous study, we identified the diverse protein expression in transient receptor potential (TRP) channels, phosphorylated phospholipase C (PLC), and the stromal interaction molecule (STIM)1 between LA and RA fibroblasts [ 59 ]. Phospholipase C (PLC), the second messenger of multiple profibrotic cytokines [ 111 , 112 ], hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), thereby producing diacylglycerol (DAG) and inositol trisphosphate (IP3).…”

“…The insets in the current traces showed the various clamp protocols. * Healthy LA versus healthy RA fibroblasts; $ HF LA versus healthy LA fibroblasts; # HF LA versus HF RA fibroblasts (adapted from the published article by Chung et al [ 59 ]).…”

Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology

“…Although myofibroblasts are known as non-excitable cells, several studies have shown Na V 1.5 sodium channel protein expression [ 8 , 9 , 10 ] and recently also the expression of Ca V 1 subfamily proteins, which mediate the L-type Ca 2+ current [ 9 , 11 , 12 ]. In the last years, there have been a considerable number of studies looking at the role of Ca 2+ signaling in myo-/fibroblast physiology, and in fibrosis-associated cardiac diseases [ 13 , 14 , 15 , 16 ].…”