Induction of Hypertension and Peripheral Inflammation by Reduction of Extracellular Superoxide Dismutase in the Central Nervous System

Abstract

Abstract-The circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central superoxide has been implicated in the regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVOs and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVOs in blood pressure regulation, we performed intracerebroventricular injection an adenovirus encoding Cre-recombinase (5ϫ10 8 particles per milliliter) in mice with loxP sites flanking the SOD3 coding region (SOD3 loxp/loxp mice). An adenovirus encoding red-fluorescent protein was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg per day), whereas intracerebroventricular injection of adenovirus encoding red-fluorescent protein had minimal effects on these parameters. Adenovirus encoding Cre-recombinase-treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production, and T-cell activation as characterized by increased circulating CD69 ϩ /CD3 ϩ cells. Deletion of CVO SOD3 also markedly increased vascular T-cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in the regulation of blood pressure, and its loss promotes T-cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli, such as angiotensin II. ⅐Ϫ by administration of membrane-targeted forms of SOD, SOD mimetics (eg, Tempol), or deletion of the gene encoding for the NADPH oxidase subunit p47phox reduces blood pressure in several experimental models of hypertension. [2][3][4] In addition, embryonic deletion of SOD3, which would be expected to increase extracellular O 2 ⅐Ϫ , augments hypertension in response to angiotensin (Ang) II or deoxycorticosterone acetate-salt challenge. 5,6 Although these studies support a role for SOD3 and oxidative stress in the genesis of hypertension, they do not address potential sites or mechanisms by which deletion of SOD3 augments hypertension. Potential sites where this enzyme could modulate blood pressure include the vasculature, the kidney, and the brain. In addition to oxidative stress, recent studies from our laboratory and others have also suggested an important role for peripheral T-lymphocyte activation and vascular inflammation in the development of Ang II-induced hypertension. The relationship between oxidative events in sites such as the central nervous system, T-cell activation, and vascular inflammation remain poorly understood.The purpose of the present studies was to explore the hypothesis that defects in brain SOD3 might participate in the development of hypertensio...

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II

“…Collectively, these data support our hypothesis that increased RAAS activity in hypertension exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation by inducing oxidative stress in the muscle. Increased RAAS activity and developed oxidative stress are involved in the pathogenesis of hypertension (12,26,55) and are a hallmark in cardiovascular diseases that often develop from prolonged hypertension. In heart failure, we (19) have previously demonstrated that oxidative stress in the muscle plays a role in exaggerating the exercise pressor reflex.…”

“…Moreover, this peptide has been known to activate NADPH oxidases, thereby triggering the production of superoxide and other reactive oxygen species (ROS) in various tissues, including skeletal muscle (13,41,51,55,57). The development of oxidative stress has also been implicated in the pathogenesis of hypertension (26,55). Superoxide functions in the neural process for encoding peripheral mechanical and thermal stimuli (18,25).…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…ROS production in vessels, as well as other organs, including the heart, kidneys and brain, likely participate in blood pressure regulation. [30][31][32] This review will focus on ROS, the vascular system and hypertension, specifically relating to the clinical significance. All vascular cell types produce ROS, including endothelial, smooth muscle, adventitial fibroblasts and perivascular adipocytes, and can be formed by many enzymes, including xanthine oxidoreductase, uncoupled nitric oxide synthase, mitochondrial respiratory enzymes and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [37][38][39][40][41][42][43][44] (Figure 1).…”

Essential fatty acids and their metabolites in the context of hypertension

“…12,13 These results are supported by the recent reports that reduction of extracellular superoxide dismutase in the central nervous system promotes T-cell activation and vascular inflammation, modulates sympathetic outflow and induces hypertension. 14 It has also been found that active oxygen species and thromboxane A 2 reduced angiotensin-II type 2 receptor-induced vasorelaxation in diabetic rats. 15 Tumor necrosis factor-a has a function in activation of polymorphonuclear leukocyte NADPH oxidase, leading to systemic oxidative stress, inflammation and the development of hypertension.…”

“…26 As the brain contains all components of the renin-angiotensin system, it is likely that low brain levels of DHA and EPA could enhance the level of angiotensin II, increasing the generation of free radicals and thereby accelerating the development of hypertension. [9][10][11][12][13][14][15][16] AA, EPA and DHA can also form precursors to anti-inflammatory compounds such as lipoxins, resolvins, protectins, maresins and nitrolipids (see Figure 1 for the metabolism of essential fatty acids) that suppress leukocyte activation, inhibit free radical generation and pro-inflammatory cytokine production, enhance NO generation and exhibit potent anti-inflammatory effects. 26,27 Hence, whenever DHA (and probably other fatty acids such as AA and EPA) levels are low in the brain (especially in the hypothalamus), the production of lipoxins, resolvins, protectins, maresins and nitrolipids will be low as well, resulting in inflammation (as a result of increased production of tumor necrosis factor-a) and the induction of hypertension.…”