LBOS 02-02 TELMISARTAN REDUCING MONOCYTE MITOCHONDRIA RESPIRATORY FUNCTION IS ASSOCIATED WITH INHIBITION OF TRANSIENT RECEPTOR POTENTIAL CHANNEL CANONICAL TYPE 3 CHANNELS IN HYPERTENSIVE RATS.

OBJECTIVE: Increased transient receptor potential canonical type 3 (TRPC3) channels have been observed in essential hypertensive patients and spontaneously hypertensive rats (SHR). Our previous study shows that mitochondrial respiratory dysfunctions of blood mononuclear cells link with cardiac disturbance in patients with early-stage heart failure. Telmisartan has beneficial effect on both hypertension and metabolic syndrome. In the present study we tested the hypothesis that telmisartan administration inhibited mitochondrial respiratory function was associated with decreased TRPC3 function in monocytes from genetic hypertensive rats (SHR).

DESIGN AND METHOD: We treated SHR and normotensive Wistar-Kyoto rats (WKYs) by telmisartan (5 mg/kg/day) for 3 months. The plasma levels of Lp-PLA2, VCAM-1, SEL-P, SEL-E, MCP-1 were measured by ELISA. Mitochondrial membrane potential changes and mitochondrial ROS production was quantified. Mitochondrial respiratory function was analyzed in a respirometer. Proteins were identified by immunoblotting.

RESULTS: H2O2-induced calcium influx was significantly elevated in monocytes from SHR compared to WKY. After TRPC3 knockdown, H2O2-induced calcium influx was significantly reduced, but overexpress TRPC3 significantly increased H2O2-induced calcium influx in monocytes from SHR compared to WKY. Long-term administration of telmisartan significantly reduced increased plasma levels of Lp-PLA2, VCAM-1, SEL-P, SEL-E and MCP-1 in SHR compared to WKY. Telmisartan and TRPC3 knockdown significantly attenuated, but over-expression of TRPC3 elevated the H2O2-induced mitochondrial ROS production. Mitochondrial respiratory function of monocyte was significantly increased in SHR compared to WKY. Chronic telmisartan treatment decreased monocytes mitochondrial respiratory function parameters. The expression of hexokinase1 (HXK1) and HXK2, a primary initiator of glycolysis, were significantly reduced in monocytes from SHR compared to WKY. Telmisartan increased HXK1 and HXK2 expression of monocytes from SHR.

CONCLUSIONS: Mitochondrial respiratory dysfunction of monocyte is associated with increased TRPC3 channels in genetic hypertension. Long-term of telmisartan inhibits increased mitochondria respiratory function of monocyte in SHR rats through a hexokinases-dependent pathway.