Frontiers in cell and developmental biology · 2026
TRPV4-linked oxidative-lysosomal stress in myocardial ischemia/reperfusion: disease-matched transcriptomics and functional analysis in OGD/R cardiomyoblasts.
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Yang Jie, Li Jincheng, Li Guanyao, Zhong Heyu, Yang Hang, Zhong Kai, Wang Fan, Huang Zhou, Huang Dongling, Wei Wanxia, Lu Xueling, Pang Guodong, Chen Yuqinlin, Zhai Yiling, Wang Wei
Аннотация
BACKGROUND: Myocardial ischemia/reperfusion (MI/R) injury involves oxidative stress, lysosomal dysfunction, and altered autophagy. TRPV4 may link Ca2+ dysregulation to these processes, but its role in lysosomal membrane permeabilization (LMP) and autophagic impairment remains unclear.
METHODS: Three disease-matched mouse-heart GEO cohorts (GSE281940, GSE130217, and GSE160516) were analyzed using limma-based differential expression, prespecified oxidative, lysosomal, and autophagy-related gene sets, cross-cohort comparisons, and within-cohort correlations. H9C2 cardiomyoblasts subjected to OGD/R were used to examine intracellular Ca2+, ROS, LMP, autophagy-related changes, inflammatory cytokine release, and cell injury after pharmacological modulation of TRPV4 and ROS.
RESULTS: All three cohorts showed clear MI/R-associated transcriptional changes. Hmox1 was consistently increased across all five prespecified contrasts, whereas Trpv4 showed modest, time-dependent changes without reaching FDR-adjusted significance. Trpv4 was positively correlated with Map1lc3b in all three cohorts (Spearman ρ = 0.73-0.83, nominal P < 0.05), while associations with oxidative and lysosomal genes were more variable. In H9C2 cardiomyoblasts, OGD/R increased TRPV4 mRNA expression, intracellular Ca2+, and ROS levels. TRPV4 inhibition reduced ROS accumulation, attenuated LMP-related changes, and decreased LC3B and p62 accumulation, whereas TRPV4 activation produced the opposite effects. NAC attenuated TRPV4 activation-induced ROS and lysosomal injury, while t-BHP partially reversed the effects of TRPV4 inhibition. OGD/R also increased IL-1β, IL-6, and TNF-α release, which was reduced by TRPV4 inhibition.
CONCLUSION: The transcriptomic data indicate a context-dependent TRPV4 response within a conserved MI/R stress background. The H9C2 cardiomyoblasts experiments support the involvement of the TRPV4-ROS-LMP pathway in lysosomal injury, impaired autophagic degradation, inflammatory responses, and OGD/R-induced cardiomyoblast injury.
METHODS: Three disease-matched mouse-heart GEO cohorts (GSE281940, GSE130217, and GSE160516) were analyzed using limma-based differential expression, prespecified oxidative, lysosomal, and autophagy-related gene sets, cross-cohort comparisons, and within-cohort correlations. H9C2 cardiomyoblasts subjected to OGD/R were used to examine intracellular Ca2+, ROS, LMP, autophagy-related changes, inflammatory cytokine release, and cell injury after pharmacological modulation of TRPV4 and ROS.
RESULTS: All three cohorts showed clear MI/R-associated transcriptional changes. Hmox1 was consistently increased across all five prespecified contrasts, whereas Trpv4 showed modest, time-dependent changes without reaching FDR-adjusted significance. Trpv4 was positively correlated with Map1lc3b in all three cohorts (Spearman ρ = 0.73-0.83, nominal P < 0.05), while associations with oxidative and lysosomal genes were more variable. In H9C2 cardiomyoblasts, OGD/R increased TRPV4 mRNA expression, intracellular Ca2+, and ROS levels. TRPV4 inhibition reduced ROS accumulation, attenuated LMP-related changes, and decreased LC3B and p62 accumulation, whereas TRPV4 activation produced the opposite effects. NAC attenuated TRPV4 activation-induced ROS and lysosomal injury, while t-BHP partially reversed the effects of TRPV4 inhibition. OGD/R also increased IL-1β, IL-6, and TNF-α release, which was reduced by TRPV4 inhibition.
CONCLUSION: The transcriptomic data indicate a context-dependent TRPV4 response within a conserved MI/R stress background. The H9C2 cardiomyoblasts experiments support the involvement of the TRPV4-ROS-LMP pathway in lysosomal injury, impaired autophagic degradation, inflammatory responses, and OGD/R-induced cardiomyoblast injury.