Abstract P239: Toll-Like Receptors 9 (TLR9) Play a Key Role in Cardiac and Vascular Dysfunction Associated With 2-Kydney 1-Clip (2K1C) Hypertension in Mice

Introduction: Renovascular hypertension is the leading cause of secondary hypertension and is also involved in the physiopathogenesis of resistant hypertension. The activation of toll-like receptors 9 (TLR9) was demonstrated to contribute to the increase in arterial pressure (AP) in spontaneously hypertensive rats. We hypothesize that the TLR9 are also activated in two-kidney one- clip (2K1C) hypertensive mice, eliciting cardiac and vascular dysfunction; therefore, contributing to the increase in AP. Methods and Results: C57BL (WT) and TLR9 knockout (TLR9_KO) mice were anesthetized with isoflurane and submitted to 2K1C hypertension by placing a silver clip (0.12 mm) around the left renal artery. After 4 weeks, the cardiac function of mice was evaluated by echocardiography in anesthetized subjects. Following, the direct AP measurement was carried out and the third-order mesenteric resistance arteries (MRA) were removed for vascular function evaluation. All data were compared to Sham-operated WT mice. The AP was remarkably elevated in 2K1C WT mice (133±2 vs 93 ± 4 mmHg), whereas this increase was partially prevented by the absence of the TLR9 (114±5 mmHg). 2K1C hypertension caused cardiac dysfunction in WT mice, displaying decreased ejection fraction (42.6±3.1 vs 52.7±1.5%), fractional shortening (10.1±0.7 vs 13.7±0.9%), stroke volume (25.9±2.2 vs 37.9±1.9 μL) and cardiac output (9.2±0.8 vs 14.6±0.8 mL/min); however, the 2K1K hypertension did not affect the cardiac function in TLR9_KO mice: ejection fraction (54.5±1.6%), fractional shortening (14.5±1.1%), stroke volume (43.4±4.6 μL) and cardiac output (15.2±1.6 mL/min). Vascular dysfunction, characterized by increased contractile response to phenylephrine (Emax: 167.2±2.2 vs 125.9±3.5%) and reduced relaxation to acetylcholine (Emax: 69.3±1.6 vs 87.6±1.4%) and sodium nitroprusside (pD2: 7.3±0.07 vs 7.9±0.05), was observed in 2K1C WT mice, but not in 2K1C TLR9_KO mice (Emax: 127.7±2.9%, 88.5±2.0% and pD2: 7.78±0.06, to phenylephrine, acetylcholine and sodium nitroprusside). Conclusions: TLR9 is involved in both cardiac and vascular dysfunctions of 2K1C mice and also in the increase of AP of this experimental model.