Abstract 18024: Tissue Transglutaminase-Mediated AT1 Receptor Posttranslational Modification Underlies Inflammatory Cytokine-Induced Hypertension and Cardiac Dysfunction

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Hypertension is a severe cardiovascular complication with elevated inflammation. Encoded by a gene whose transcription is activated by inflammatory cytokines, tissue transglutaminase (TG2) is known to stabilize the angII receptor AT1 and contribute to pathogenesis of preeclampsia. We hypothesize that TG2 is an essential effector of inflammation-induced hypertension and cardiac dysfunction by stabilizing AT1 receptors. To test this, we applied the TG2-specific inhibitor ERW1041E (0.125mg/day) to a hypertension mouse model established by 14-day introduction of inflammatory cytokine LIGHT/TNFSF14 (4ng/day). Hypertensive features including blood pressure increase (PBS=106±4, LIGHT=145±5 vs LIGHT+ERW1041E=105±12mmHg), proteinuria (PBS=0.02±0.01, LIGHT=0.17±0.05 vs LIGHT+ERW1041E=0.03±0.01mg albumin/mg creatinine), AT1-AA production (PBS=1.6±0.3, LIGHT=19.6±3.7 vs LIGHT+ERW1041E=9.4±1.7U/ml), elevation of plasma transglutaminase activity (PBS=3.8±1.1, LIGHT=16.7±0.5 vs LIGHT+ERW1041E=8.7±0.6mU/ml), and echocardiographic changes including EF (PBS=49±2%, LIGHT=63±2% vs LIGHT+ERW1041E=53±5%) and FS (PBS=25±1%, LIGHT=33±1% vs LIGHT+ERW1041E=28±3%) were significantly ameliorated in mice co-injected with ERW1041E (p<0.05, n=4-5). Essential role of TG2 was further confirmed by finding that LIGHT-induced hypertension and echo changes were prevented in TG2-deficient mice compared to controls (BP: 114±4 vs 154±11mmHg, EF: 53±4% vs 69±9%, FS: 27±3% vs 39±8%, n=3-4, p<0.05). Using Western blot and immunofluorescence, we discovered LIGHT introduction lead to a significant increase in renal TG2 and TG-modified AT1 receptor, which were abrogated by TG inhibitor. Finally, we found that LIGHT directly induced a TG2 dependent cellular AT1 receptor accumulation. Our data indicate a requirement for TG2 in inflammation-induced hypertension and possibility of TG2 inhibitor ERW1041E as a novel antihypertensive. Our findings also suggest inflammatory cytokines may directly elevate angII sensitivity by activating TG2-mediated AT1 receptor accumulation.

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