Hyperglycemia Revisited: Deciphering Early Signaling Responses with ER-Stress-Related Effects and Connexins in the Spotlight

Diabetes constitutes one of the major prevailing diseases worldwide, with cardiovascular pathologies as the primary cause of the morbidity and mortality rates reported. Hyperglycemia, the principal hallmark of diabetes, results from accumulated glucose levels. Although molecular mechanisms induced by high glucose (HG) have been extensively investigated, their complex interconnections and immediately activated signaling pathways remain unresolved. Hence, in the present study, we tried to identify effectors directly responsive to HG, focusing on the early activated signal transduction routes in H9c2 cardiac cells. MTT analysis illustrated the apoptosis- and oxidative-stress-mediated detrimental effect of 25 mM glucose on H9c2 viability. Initiation of oxidative-stress-related mechanisms was corroborated via detection of POR and HOX-1 augmented expression levels. Additionally, western blot analysis demonstrated activation of p38-MAPK and ERK1/2, along with autophagy- and ER-stress-related markers. Of note, involvement of biomechanical signaling players was also revealed, with Piezo1, connexin 43 and GJA1-20k expression being gradually enhanced. Intriguingly, ERK1/2 and ER-stress-associated effectors were observed to mediate connexin 43 and GJA1-20k upregulation. With connexins playing a nodal biological role in diabetes-driven cardiovascular pathologies, exploring potential modulatory effectors may provide insight into development of promising therapeutic interventions, favoring preservation of cell function and systems homeostasis under hyperglycemic conditions.