Abstract 12759: Aldosterone Promotes Vascular Inflammation Mediated by Trans-Activation of Caveolin/angiotensin-ii- Receptor-Type-1/tyrosine Kinase Pyk2 Pathway
Background Aldosterone (Ald), known as Na-sensitive hypertensive hormone, also causes cardiovascular inflammation/fibrosis. Angotensin-II (Ang-II) cause inflammatory cardiovascular disease. Ald and Ang-II were thought to be synergically involved in vascular inflammation, but details of the mechanism have not been well understood. Ald has a non-genomic effect without transcription, which is related to vascular inflammation through ROS/Tyrosine kinase Src/JNK pathway. Caveolae is a micro-domain with low fluidity in plasma-membrane, where signaling molecules like GPCR are highly accumulated. We here show that Aldo-induced inflammatory action is mediated by Caveolin/Angiotensin-II-Receptor Type-1 (AT-1R).
Methods and Results: 12-week-old mice were infused Ang-II or Ald through subcutaneous osmotic pump and perivascular fibrosis was stained with Masson-trichrome stainning. Infusion of low dose Ang-II (100 ng/kg/day), or low dose of Ald (200ng/kg/day) did not causes perivascular fibrosis, but combined infusion of those two caused the fibrosis. Cultured aortic Vascular Smooth muscle cells (VSMC) was stimulated with Aldo (100 nM). In a few minutes after stimulation, Ald-associated MR bound to HSP90 and Aldo/MR/HSP90 complex translocated to the Caveolae at plasma-membrane, by HSP90-binding to Caveolin-1. HSP-90 recruited tyrosine kinase, PYK2 and PYK2 activated membrane-bound Src, leading to activate ROS/JNK-pathway. Also, stimulation with Ald increased the Caveolin-1 level and Caveolae area at plasma-membrane and the AT1-R accumulation in the Caveolae. Treatment with AT1-R-blocker or AT1-R-deficiency abolished Aldo-induced PYK2/JNK activation. ∼10nM of Ang-II was detected in the conditioned medium of VSMC and 10nM of Ang-II plus 100nM Ald induced activation of PYK2/JNK, but only10 nM of Ang-II did not. Neutralization antibody against Ang-II abolished Ald-mediated activation of PYK2/JNK. Taken together, Ald increased expression level of AT1-R on the plasma-membrane, which enables VSMC to respond to low dose of Ang-II to transmit JNK/PYK2-mediated inflammatory signaling.
Conclusion: Aldo-induced vascular inflammation is mediated by Caveolin-1/AT1-R/PYK2-signaling.
- © 2011 by American Heart Association, Inc.