Dose- and Time-Dependent Modulation of Cx43 and Cx45 Expression and Gap Junction Conductance by Resveratrol

Plant extracts are rich in various bioactive compounds, such as polyphenols, flavonoids, tannins, terpenoids, phenolic acids, saponins, alkaloids, and polysaccharides. Antioxidant polyphenols are increasingly attracting attention, not only as dietary components but also as valuable food industry byproducts. Resveratrol, present in a wide range of plants, is well recognized for its diverse biological activities, including antioxidant, antitumor, cardioprotective, and neuroprotective effects. Given the importance of intercellular communication in these physiological processes, gap junctions (GJs) composed of connexin (Cx) family proteins are of particular interest because they provide a direct pathway for electrical and metabolic signaling and are key players in maintaining normal organ function and cell development. Aberrations of GJ intercellular communication (GJIC) may result in the progression of cardiovascular and neurological diseases and tumorigenesis. Cx43 and Cx45 play crucial roles in cardiac excitation and contraction, and alterations in their expression are associated with disrupted impulse propagation and the development of arrhythmias. In this study, for the first time, we performed a comparative analysis of the effect of resveratrol on Cx43 and Cx45 GJIC using molecular modeling, a dual whole-cell patch-clamp technique to directly measure GJ conductance (g_j), and other approaches. Our results revealed that resveratrol accomplished the following: (1) inhibited GJ g_j in Cx43- but enhanced it in Cx45-expressing HeLa cells; (2) exerted dose- and time-dependent changes in Cx expression and plaque size; (3) reduced cell viability and proliferation; (4) and altered Cx43 phosphorylation patterns linked to gating and plaque stability. Overall, resveratrol modulates GJIC in a dose-, time-, and connexin type-specific manner.