Abstract 855: Critical Role of Apoptosis Signal-Regulating Kinase 1 in Vascular Endothelial Dysfunction of NO-Deficient Hypertension
OBJECTIVE: Treatment with N-nitro-L-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, induces hypertension and vascular injury, although the exact mechanism is unknown. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), the mitogen-activated protein kinase kinase kinase, in vascular injury of NO-deficient hypertension induced by L-NAME.
METHODS: L-NAME was orally administered to ASK1 deficient and C57BL/6J (WT) mice for 4 or 8 weeks. Vascular endothelial function was examined in carotid artery, preconstricted by phenylephrine(10−7M) or prostaglandin F2α(10−5M). Coronary arterial remodeling was estimated by pathological examination.
RESULTS: Under basal condition, there was no significant difference in blood pressure, vascular endothelial function and vascular structure between WT and ASK1 deficient mice. L-NAME treatment increased blood pressure of WT and ASK1 deficient mice to a similar extent throughout treatment, indicating the minor role of ASK1 in blood pressure elevation by NO deficiency. L-NAME treatment significantly impaired Ach (10−7×10−4M)-induced carotid arterial relaxation in WT mice (P<0.01), while did not significantly impair it in ASK1 deficient mice, indicating the major role of ASK1 in vascular endothelial dysfunction by L-NAME. No difference was found in SNAP (NO donor)-induced vascular relaxation between WT and ASK1 deficient mice, indicating the minor role of ASK1 in endothelium-independent relaxation. Histological examination indicated that coronary arterial thickening (136±11 vs 227±21 %; P<0.01) and perivascular fibrosis (73±15 vs 251±21 %; P<0.01) induced by L-NAME was much less in ASK1 deficient mice than in WT mice, indicating the involvement of ASK1 in vascular remodeling by L-NAME. L-NAME treatment in WT mice reduced eNOS activity by 36% (P<0.01) and serum NOx by 34% (P<0.01), while did not reduce eNOS activity or NOx in ASK1 deficient mice.
CONCLUSIONS: Our results provided the first evidence that ASK1 plays a key role in vascular endothelial dysfunction and remodeling induced by NO deficiency and that ASK1 is involved in suppression of eNOS activity by L-NAME. Thus, ASK1 may be the promising therapeutic target of vascular disesess induced by NO deficiency.