Inflammatory molecule plays an important role in the pathophysiology of hypertension. Recently we showed that TLR4 inhibition in the brain attenuates hypertension. In this study we demonstrate that ANGII induced ER stress in the heart is attenuated in mice lacking the gene for TLR4. In addition, we show that ANGII induced cardiac hypertrophy is blocked by ER stress inhibitor.
Method: TLR4 knock-out (KO) mice and wild type (WT) controls were implanted with telemetry probes for mean arterial pressure (MAP) measurements. After collecting baseline MAP and left ventricular function using echocardiography, osmotic minipump containing ANGII (200ng/kg/min) or vehicle (saline) was implanted for 14 days. In another group, C57BL6 mice were injected with ER stress inhibitor 4-PBA (150mg/kg bw) given intraperitoneally with and without ANGII. At the end of the study, mice were sacrificed the LV tissue removed and analyzed for gene of interest using RT-PCR and Western blotting.
Results are tabulated. The real-time PCR values are shown as αCT values (18S - the gene of interest).
Conclusions: 1) ANGII infusion induces cardiac hypertrophy and ER stress. 2) Mice lacking the gene for TLR4 had attenuated cardiac hypertrophy and ER stress in response to ANGII. 3) ER stress inhibitor protect against ANGII induces cardiac hypertrophy. 4) TLR4 at least in part contributes to ANG II induced cardiac hypertrophy and ER stress.