In:
Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. Suppl_1 ( 2018-09)
Abstract:
The prevalence of hypertension is growing steadily with mortality reaching 30,221. While effective blood pressure reduction therapy exists, the underlying pathophysiology leading to vascular remodeling remains poorly understood. Hypertension is a risk factor for abdominal aortic aneurysms (AAA) which when ruptured has 80% mortality. Surgery is the only treatment due to insufficient understanding of the disease process. Mitochondrial dysfunction has been implicated in various cardiovascular diseases but the role of mitochondrial dynamics, a mechanism regulating mitochondrial homeostasis, is under-investigated in hypertension and aneurysm. Our data shows that enhancement of mitochondrial fission via a GTPase, Drp1, in vascular smooth muscle cells (VSMCs) is involved in hypertensive vascular remodeling and aneurysm. In vitro, AngII induced transient mitochondrial fission (2-4 h) and enhanced mitochondrial ROS production in rat aortic VSMCs. Mitochondrial fission, mito-ROS generation, total cell protein, cell volume and extracellular collagen increased by 100 nM AngII were all attenuated in VSMCs by pretreatment with adenovirus encoding Drp1 siRNA/control non-silencing RNA or mdivi1, a Drp1 inhibitor. In vivo, male C57BL/6 mice were infused with AngII (1000ng/kg/min) for 2 weeks (hypertensive remodeling model) +/- mdivi1 (25 mg/kg ip every other day) or infused with AngII for 4 weeks with beta-aminopropionitrile in the drinking water (AAA model) +/- mdivi1 (25 mg/kg ip 3x per week). In the 2-week AngII model, mdivi1 suppressed left ventricular hypertrophy, vascular hypertrophy and perivascular fibrosis induced by AngII in aorta, heart and kidney, independent of blood pressure. In the AAA model, mdivi1 attenuated aneurysm development (External AA diameter (mm) Mean±SEM: 2.15±0.13 vs 1.49±0.07 (, p 〈 0.01). Reduced KDEL and nitro-tyrosine staining in aorta (4w model), coronary and renal arteries (2w) in mdivi1 treated mice, suggests attenuation of ER stress and oxidative stress, respectively. These data suggest that inhibition of mitochondrial fission prevents AngII-induced cardiovascular remodeling and aneurysm development independently of hypertension via ER stress/mito-ROS mechanisms.
Type of Medium:
Online Resource
ISSN:
0194-911X
,
1524-4563
DOI:
10.1161/hyp.72.suppl_1.061
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
2094210-2
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