Paper
Tongyang Huoxue Decoction (TYHX) synergistically regulates calcium homeostasis and mitochondrial unfolded protein response in ischemia-reperfusion injured sinus node cells via SERCA2a
Published Jan 1, 2025 · Jinfeng Liu, Xing Chang, Qin Zhang
Integrative Medicine Discovery
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Abstract
Background: Tongyang Huoxue Decoction (TYHX) can modulate calcium homeostasis and mitochondrial quality management to safeguard sinus node function. Nonetheless, the precise chemical process remains unclear. This study aimed to verify the upstream regulatory influence of SERCA2a on the enhancement of calcium homeostasis and mitochondrial unfolded protein response (mtUPR) in sinus node cells (SANCs) by TYHX, while elucidating the protective mechanism of TYHX on SNC activity. Methods: In vitro models of sh/ad-SERCA2a and si-β-tubulin were established, and TYHX was employed to intervene in each cell group. Various approaches were employed to detect functions including mitochondrial membrane potential, mitochondrial respiration, oxidative stress, mitochondrial biosynthesis, and mitochondrial autophagy and UPR. In vivo confirmation that TYHX suppresses apoptosis and inflammatory injury. Results: I/R injury led to diminished SANCs activity, compromised mitochondrial membrane potential, reduced mitochondrial respiratory function, and heightened oxidative stress. This further impeded mitochondrial production, destabilized the proteome structure, triggered the mtUPR, and inhibited mitochondrial autophagy, thereby upsetting the dynamic equilibrium of the mitochondrial quality control network. Furthermore, I/R injury intensified intracellular calcium excess and worsened oxidative stress damage. Conversely, TYHX intervention mitigated intracellular calcium overload, augmented mitochondrial antioxidant capacity, stimulated mitochondrial autophagy, and decreased the mtUPR. Sh-SERCA2a counteracted the regulatory influences of TYHX on calcium homeostasis, mitochondrial biogenesis, mtUPR, mitochondrial autophagy, and apoptosis. Conversely, ad-SERCA2a exerted minimal influence on the efficacy of TYHX. SERCA2a is a major target protein for TYHX to demonstrate its efficacy. When tubulin expression was minimal, there was no statistically significant difference in the expression levels of mitochondrial autophagy, mitochondrial biosynthesis, calcium homeostasis regulation, and mtUPR between the sh-SERCA2a and ad-SERCA2a groups. This indicates that the normal expression of tubulin is essential for SERCA2a to enhance the efficiency of TYHX. Tubulin may serve as an upstream regulatory molecule of SERCA2a. In vivo tests confirmed that TYHX may suppress apoptosis and mitigate cellular inflammatory damage. Conclusion: TYHX preserved intracellular calcium equilibrium, mitigated mitochondrial oxidative stress, sustained mitochondrial stability, enhanced mitochondrial biosynthesis, suppressed the mtUPR, facilitated mitochondrial autophagy, and inhibited apoptosis via β-tubulin-SERCA2a, thereby safeguarding sinus node functionality from I/R injury.
TYHX protects sinus node function from ischemia-reperfusion injury by regulating calcium homeostasis, mitochondrial quality management, and apoptosis through SERCA2a and -tubulin.
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