Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.

Background and Study Aims: Video capsule endoscopy and double-balloon enteroscopy (DBE) are novel methods of enteroscopy. The aim of this investigation was to compare the value of CE and DBE in the diagnosis of small-intestinal pathology. Patients and Methods: Thirteen patients with gastrointestinal bleeding of obscure origin and nine patients with known gastrointestinal polyposis were examined using antegrade or retrograde DBE, and the most distal or proximal site in the explored small intestine was marked by submucosal injection of sterilized ink. The patients were then evaluated by CE. Video images obtained by CE were reviewed by an observer who was blinded to the DBE findings. Results: DBE identified positive findings in 12 patients (54.5 %). CE identified positive findings in the area explored by DBE in eight patients (36.4 %), and in the unexplored area in 11 patients (50.0 %). The overall diagnostic yield in the area explored by DBE did not differ between the two procedures. The enteroscopic findings in the area explored by DBE were concordant in 12 of 13 patients with gastrointestinal bleeding of obscure origin. In patients with polyposis, the diagnoses were discordant in three patients, in whom CE failed to detect any polyp. In two of three polyposis patients with concordant positive findings, DBE detected a larger number of polyps than CE did. Conclusions: DBE appears to be superior to CE in the diagnosis of small-intestinal polyps, whereas the value for diagnosing gastrointestinal bleeding of obscure origin is similar in the two procedures.

Capsule endoscopy has shown that non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine. The aim of this study was to determine the prevalence of NSAIDs enteropathy in subjects indicated for double-balloon endoscopy (DBE). The Japanese Study Group for Double-Balloon Endoscopy (JSG-DBE) established a database for the practical use of DBE in the Japanese population during a 2-year period from 2004 to 2005. Using this database, we identified subjects who had been taking NSAIDs within a month prior to DBE (NSAIDs group) and those free from NSAIDs use (control group). The clinical background and DBE findings were compared between the two groups. Among 1035 patients registered in the JSG-DBE database, 61 subjects were classified as the NSAIDs group and 600 served as the control group. Patients in the NSAIDs group were older (62+/-18 versus 51+/-19 years, p<0.0001) and gastrointestinal bleeding was a more frequent indication for DBE (79% versus 44%, p<0.001) compared with in the control group. Non-specific mucosal breaks were detected by DBE in 31 patients in the NSAIDs group (51%) and 29 patients in the control group (5%, p <0.0001). Aspirin was less frequently prescribed and cardiovascular disease was a less frequent indication for NSAIDs use in patients with mucosal breaks than in those without breaks. In the cases indicated for enteroscopy, NSAIDs enteropathy occurred in half of the patients taking NSAIDs. Aspirin seems to be less harmful to the small intestine than other NSAIDs.

Emerging evidence suggests that in addition to being the ‘power houses’ of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9 in a similar fashion to bacterial DNA stems from evolutionarily conserved similarities between bacteria and mitochondria. mtDNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. PE (pre-eclampsia) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The aetiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells, and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulates TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and IUGR (intra-uterine growth restriction). The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE, and anti-TLR9 treatments may be promising in the management of the disease.

A contributing factor to increased peripheral resistance seen during hypertension is an increased production of endothelium-derived contractile factors (EDCFs). The main EDCFs are vasoconstrictor prostanoids, metabolites of arachidonic acid (AA) produced by Ca²⁺-dependent cytosolic phospholipase A₂(cPLA₂) following phosphorylation (at Ser⁵⁰⁵) mediated by extracellular signal-regulated kinase (ERK1/2) and cyclooxygenase (COX) activations. Although endoplasmic reticulum (ER) stress has been shown to contribute to pathophysiological alterations in cardiovascular diseases, the relationship between ER stress and EDCF-mediated responses remains unclear. We tested the hypothesis that ER stress plays a role in EDCF-mediated responses via activation of the cPLA₂/COX pathway in the aorta of the spontaneously hypertensive rat (SHR). Male SHR and Wistar-Kyoto rats (WKY) were treated with ER stress inhibitor, tauroursodeoxycholic acid or 4-phenlybutyric acid (TUDCA or PBA, respectively, 100 mg·kg⁻¹·day⁻¹ip) or PBS (control, 300 μl/day ip) for 1 wk. There was a decrease in systolic blood pressure in SHR treated with TUDCA or PBA compared with control SHR (176 ± 3 or 181 ± 5, respectively vs. 200 ± 2 mmHg). In the SHR, treatment with TUDCA or PBA normalized aortic (vs. control SHR) 1) contractions to acetylcholine (ACh), AA, and tert-butyl hydroperoxide, 2) ACh-stimulated releases of prostanoids (thromboxane A₂, PGF_2α, and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA₂and ERK1/2, and 5) production of H₂O₂. Our findings demonstrate a novel interplay between ER stress and EDCF-mediated responses in the aorta of the SHR. Moreover, ER stress inhibition normalizes such responses by suppressing the cPLA₂/COX pathway.