Excessive sympathetic activity has a crucial role in the initiation and progression of chronic structural alterations in the heart and vessels associated with hypertension. Angiotensin II type 1a receptors (AT 1a R) in paraventricular nucleus (PVN) are involved in sympathetic overdrive and hypertension. The present study was designed to investigate the cardiovascular beneficial effects of the AT 1a R gene silence in the PVN in hypertension. The PVN microinjection of recombinant adenoviral vectors expressing either artificial microRNA (amiRNA) targeting AT 1a receptors (Ad-miR-AT 1a ) or control microRNA (Ad-miR-Con) were carried out in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. The vectors were labels with green fluorescent protein (GFP). The successful amiRNA interference was confirmed by the AT 1 receptors reduction and the GFP expression in the PVN. Significant depressor effects were observed from day 5 to day 20 after Ad-miR-AT 1a treatment in SHR. Ad-miR-AT 1a treatment decreased the ratio of left ventricular weight to body weight, cross-sectional areas of myocytes, myocardial fibrosis, media thickness, and the media/lumen ratio of the aorta and the mesenteric artery in SHR. The amiRNA interference reduced the basal sympathetic activity, cardiac sympathetic afferent reflex, plasma norepinephrine and plasma angiotensin II in SHR. These results indicate that amiRNA interference targeting AT 1a R in the PVN decreases arterial blood pressure, blunts sympathetic activity and improves myocardial and vascular remodeling in SHR.Gene Therapy ( Keywords: RNA interference; AT 1 receptors; hypertension; sympathetic activity; myocardial fibrosis; vascular remodeling INTRODUCTION As a worldwide challenge, hypertension is a powerful independent risk factor for the development of cerebrovascular disease, myocardial infarction, heart failure and peripheral artery disease. Sympathetic overdrive has a key role in the progression of hypertension and related pathological changes. 1,2 Sympathectomy surgery in spontaneously hypertensive rats (SHR) attenuates cardiac fibrosis and hypertension. 3 Central sympathetic deactivation has been considered as an important strategy for arresting hypertension and regressing-related cardiac structural alterations. 4,5 Paraventricular nucleus (PVN) is critical in the integration of sympathetic outflow and cardiovascular activity via its projections to rostral ventrolateral medulla and intermediolateral column of spinal cord. 6 Inhibiting the PVN dramatically reduces sympathetic vasomotor tone, 7 whereas activating the PVN increases sympathetic outflow in SHR. 8 Bilateral electrolytic lesions of the PVN attenuate the sympathetic activity and the development of hypertension in SHR. 9,10 These results indicate the importance of the PVN in the development and progression of hypertension in SHR.It has been found that the angiotensin II type 1 receptors (AT 1 R) in the PVN are increased in SHR 11 and renovascular hypertensive rats. 12 Our recent studies have shown that angio...

No abstract