Tannic Acid is a Tissue‐Specific Dual Modulator of Angiotensin Type 1 Receptor and Low‐Density Lipoprotein Receptor in Rat Aortic Vascular Smooth Muscle and Liver Epithelial Cells: An Insight into the “French Paradox”

Abstract

“French Paradox,” suggests the protective effect of various polyphenols present in red wine against cardiovascular diseases. Although tannic acid (TA), one such hydrolyzable polyphenol, has diverse pharmacological effects, it's cardioprotective mechanism is not well understood. In this study, we have investigated the effects of tannic acid on angiotensin type 1 receptor (AT1R) and low‐density lipoprotein receptor (LDLR), two major players associated with cardiovascular disorders such as hypertension and hyperlipidemia. Under normal culture conditions, exposure of the primary rat aortic vascular smooth muscle cells (RASMCs) and rat liver epithelial (WB) cells to TA inhibited cell‐surface expression of AT1R an effect that is time and dose dependent without any significant change in receptor affinity to angiotensin II (AngII). The inhibitory effect of TA was reversible after providing a TA‐free media for 24 hours. The inhibition of AT1R was further correlated with a significant decrease in the AngII‐mediated release in intracellular calcium. The down‐regulation of AT1R protein is associated with an inhibition of AT1R mRNA expression. In these cells, TA phosphorylated p42/44 MAP Kinases. Nevertheless, pretreatment with a MEK‐specific inhibitor PD98059 prevented TA mediated down‐regulation of the AT1R suggesting a role for MAP Kinase. Moreover, AG1478, an EGFR inhibitor blocked TA mediated MAP kinase activation and down‐regulation of AT1R. Under similar conditions, we observed a significant increase in TA mediated LDLR expression in WB cells, which was not observed in RASMCs. Furthermore, proprotein convertase subtilisin/kexin type 9 (PCSK9), a crucial enzyme responsible for LDLR turn over, was decreased upon TA exposure in WB cells whereas increased in RASMCs. The inverse correlation between LDLR and PCSK9 expression suggests that TA induced LDLR expression is at least in part through preventing PCSK9‐mediated degradation of LDLR protein in these cells. Taken together, the present study show for the first time that TA mediated activation of MAP Kinase through EGFR is critical for the regulation of AT1R and LDLR in RASMCs and WB cells, which can simultaneously prevent hypertension and hyperlipidemia through distinctly targeting AT1R and LDLR, therefore, providing the mechanistic insight into the “French Paradox.”