Improvement of Vascular Function by Knockdown of Salusin-β in Hypertensive Rats via Nitric Oxide and Reactive Oxygen Species Signaling Pathway

Abstract

PurposeSalusin-β, a multifunctional vasoactive peptide, has a potentially important function in the pathological development of hypertension. However, the exact functional role of salusin-β and the underlying mechanism in this process are still not fully understood. The current study aimed to investigate the effects of silencing salusin-β on vascular function and vascular remodeling, as well as its signaling pathways in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).MethodsSilencing salusin-β was performed by caudal vein injection of adenovirus expressing salusin-β short hairpin RNA (shRNA). Acetylcholine (ACh)-induced endothelium-dependent relaxation was used to evaluate vasodilator function, and high K+ solution-induced constriction was used to evaluate vasoconstriction function.ResultsSalusin-β levels in plasma and its protein expression in mesenteric artery (MA), coronary artery (CA), and pulmonary artery (PA) of SHR were higher than those in WKY. The salusin-β level and expression were decreased effectively by salusin-β shRNA. Knockdown of salusin-β decreased arterial blood pressure (ABP) and high K+ solution-induced vascular constrictions, and improved the endothelium-dependent relaxation and vascular remodeling in SHR. The improved effect of silencing salusin-β on ACh-induced relaxation in SHR was almost blocked by the nitric oxide synthase (NOS) inhibitor L-NAME. Compared to WKY, the endothelial NOS (eNOS) activity and level, and nitric oxide (NO) level were decreased, while NAD(P)H oxidase activity and reactive oxygen species (ROS) levels in MA, CA, and PA of SHR were increased, which were all redressed by salusin-β knockdown.ConclusionThese results indicate that knockdown of salusin-β improves endothelium-dependent vascular relaxation and vascular remodeling and decreases ABP and vasoconstriction in SHR, which might be accomplished by increasing eNOS activation and NO release while inhibiting NAD(P)H oxidase derived-ROS generation. Scavenging salusin-β improves vascular function and then prevents the development and progression of vasculopathy of hypertension.

Artemisinin Improves Acetylcholine-Induced Vasodilatation in Rats with Primary Hypertension

“…The systolic blood pressure was obtained by averaging 10 measurements as described in our previous reports. 28,29 Heart Rate and Mean Arterial Pressure Recording Rats were anaesthetized by intraperitoneal injection with urethane (800 mg/kg), and then the right carotid artery was cannulated. A pressure transducer (MLT0380, ADInstruments, Australia) linked to a Powerlab data acquisition system (8SP, ADInstruments, Australia) was used to continuously record the arterial blood pressure, from which the heart rate and mean arterial pressure under anaesthesia were calculated using Chart software.…”

“…NAD(P)H oxidase activity and superoxide anion levels of the arteries after incubation with different chemicals were measured using an enhanced lucigenin-derived chemiluminescence method as previously reported. 28,33 Briefly, the light emissions produced from the reaction between lucigenin (5 μM) and the superoxide anions in the artery tissue homogenate supernatant were recorded by a luminometer (20/20n, Turner, CA, USA) once every minute for 10 minutes to measure the superoxide anion levels. For the NAD(P)H oxidase activity measurement, the NAD(P)H substrate (100 μM) was added to the medium to react with NAD(P)H oxidase to generate superoxide anions before the light emissions were detected by the luminometer.…”

“…26 Furthermore, we recently found that decreased eNOS-NO release and increased ROS production in endothelial cells are important factors in attenuating endothelium-dependent vascular relaxation in primary hypertension. 27,28 However, the effect of artemisinin on endothelial dysfunction in hypertension remains unknown.…”

Knockdown of Salusin‐β Improves Cardiovascular Function in Myocardial Infarction‐Induced Chronic Heart Failure Rats

“…Studies have found that salusin- β is involved in endothelial injury and dysfunction in diabetes mellitus [ 30 , 33 ]. Recently, we also found that salusin- β plays important roles in regulating endothelial dysfunction in spontaneously hypertensive rats [ 34 , 35 ]. It has been reported that salusin- β expression in the paraventricular nucleus (PVN) in aged spontaneously hypertensive rats with heart failure is dramatically increased, and salusin- β knockdown in the PVN attenuates sympathetic excitation and hypothalamic inflammation as well as cardiac and vascular dysfunction [ 36 ].…”

Reactive Oxygen Species Are Essential for Vasoconstriction upon Cold Exposure

“…ROS played a vital role in vasoconstriction after cold exposure. Pan et al [ 8 ] found that increasing endothelial nitric oxide synthase (eNOS) activation and NO release and inhibiting NADPH oxidase-derived ROS generation could improve vascular function, preventing the development and progression of hypertension vasculopathy. However, it is not clear how ROS regulate vasoconstriction or where ROS exert their effects.…”