Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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There are many cellular/molecular mechanisms by which RAS hyperactivity

and oxidative stress promote neural inflammation and autonomic unbalance.

Increased gene and protein expression of different components of the vasoconstrictor

axis of the renin-angiotensin system as the angiotensinogen, angiotensin converting

enzyme and AT1 receptor were described in the brain of hypertensive animals

[ 49 , 53 , 56 , 57 ]. Both angiotensin II, via AT1 receptor, and the availability of

pro- inflammatory cytokines increase cytosolic calcium concentration through the

activation of phospholipase A2, which leads to inositol 3-phosphate production and,

subsequently, calcium release from the endoplasmatic reticulum. Elevated cytosolic

calcium concentration induces protein kinase C activation that phosphorylates ser-

ine 303, 304 and 328 autoinhibitory domains of p47phox, a regulatory subunit of

NADPH oxidase. These post-translational modifications allow p47phox migration

from cytosol to cell membrane, where it is assembled to others NADPH oxidase’s

subunits, as the catalytic subunit gp91phox, releasing superoxide anions [ 44 , 50 , 58 ,

59 ] and causing neuronal activation.

In addition to increase the neuronal activity, reactive oxygen species also stimu-

late redox-sensitive signaling pathways, the mitogen-activated protein kinases

(MAPK). In the PVN and RVLM angiotensin II induces p42/44 MAPK phosphory-

lation therefore increasing the activity of several transcriptional factors, such as

CREB, AP-1 and NF-kB.  Upregulation of these transcriptional factors trigger a

positive feedback mechanism between oxidative stress, inflammation and angio-

tensin II, since it increases gene expression of NADPH oxidase’s subunits, pro-

inflammatory cytokines (Tumor necrosis factor-alpha, Interleukine-6 and

Interleukine-1beta) as well as the gene expression of RAS’s components (angioten-

sinogen, angiotensin converting enzyme and AT1 receptor), amplifying the deleteri-

ous effect on autonomic areas.

In the NTS, reactive oxygen species are shown to attenuate NA’ stimulation,

since these neural connections are positively modulated by nitric oxide and the reac-

tive oxygen species reduce nitric oxide availability by nitric oxide synthase uncou-

pling (see sections below). Within the PVN preautonomic neurons, reactive oxygen

species reduce nitric oxide availability and, consequently, NR1 subunit of NMDA

receptor nitrosylation, an important mechanism for the inactivation of local gluta-

matergic signaling. Thus, reactive oxygen species increase neuronal activity, lead-

ing to baroreflex dysfunction and sympathetic hyperactivity [ 45 , 48 , 60 – 62 ].

Directly related to the angiotensin II-induced neuronal inflammation, microglia

activation was shown to be an important source for pro-inflammatory cytokines and

reactive oxygen species in the brain of hypertensive individuals [ 63 , 64 ]. In the

neurogenic hypertension induced by chronic angiotensin II infusion or systemic

inflammation, Shi et al. [ 64 ] and Wu et al. [ 65 ] have shown microglial activation

within the PVN and RVLM, marked generation of pro-inflammatory cytokines and

augmentation of both plasma norepinephrine content and blood pressure levels. In

the PVN of the adult SHR we recently showed robust microglia activation and

marked increase in the local synthesis of pro-inflammatory cytokines, which are

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