Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat

Nomoto, Tatsuya; Okada, Takashi; Shimazaki, Kuniko; Yoshioka, Toru; Nonaka-Sarukawa, Mutsuko; T, Ito; Takeuchi, Koichi; Ki, Katsura; Mizukami, Hiroaki; Kume, Akihiro; Ookawara, Susumu; Ikeda, Uichi; Katayama, Yasuo; Ozawa, Keiya

doi:10.1038/gt.2008.151

Cited by 27 publications

(19 citation statements)

References 45 publications

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“…For instance, co-infusion of the anti-inflammatory cytokine IL-10 with Ang II significantly reduced the Ang II-induced increase in systolic BP in WT-M mice 32 . Moreover, systemic overexpression of IL-10 reduced BP in the stroke-prone spontaneously hypertensive male rat 33 and the male Dahl salt-sensitive rat 34 and overexpression of IL-10 specifically in the paraventricular nucleus of the male mouse, attenuated hypertension induced by chronic Ang II infusion 35 .…”

Section: Discussionmentioning

confidence: 95%

Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

et al. 2014

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Studies suggest T cells modulate arterial pressure. Since robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T cell modulation of angiotensin II (Ang II)-induced increases in mean arterial pressure (MAP) in male (M) and female (F) wild type (WT) and recombination-activating-gene-1-deficient (Rag1−/−) mice. Sex-differences in peak MAP in WT were lost in Rag1−/− mice [mmHg: WT-F, 136±4.9 vs. WT-M, 153±1.7; P<0.02; Rag1−/−-F, 135±2.1 vs. Rag1−/−-M, 141±3.8]. Peak MAP was 13 mmHg higher after adoptive transfer of male (CD3M→Rag1−/−-M) vs. female (CD3F→Rag1−/−-M) T-cells. CD3M→Rag1−/−-M mice exhibited higher splenic frequencies of pro-inflammatory interleukin-17A (2.4-fold) and tumor-necrosis factor-α (2.2-fold)-producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10 while CD3F→Rag1−/−-M mice displayed a higher activation state in general and T-helper 1-biased renal inflammation. Greater T cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to Ang II if the T cell donor was male but not female and these sex differences in T cell subset expansion and tissue infiltration were maintained for 7–8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension is distinct between the sexes and needs to be understood to improve therapeutics for hypertension-associated disease in both men and women.

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Section: Discussionmentioning

confidence: 95%

Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

et al. 2014

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“…MAP then increases to prepregnancy baseline levels at GD 14 and remains stable until term as HR declines back to baseline. This pattern appears to be linked to specific changes in placental development; however, the regulatory steps initiating the drop and subsequent gain in gestational MAP are not defined and could be due to maternal effects such as decidualization or decidual cytokine production [24][25][26]. In the current study, we hypothesized that the pregnant Rag2 À/À females would have normal circulatory regulation due to normally functioning NK/uNK cells, whereas pregnant NOD.scid females would have increased blood pressure due to their deficit in NK cell function.…”

Section: Introductionmentioning

confidence: 93%

Cardiovascular Adaptations of Pregnancy in T and B Cell-Deficient Mice

Burke

Barrette

Carter

et al. 2011

Biology of Reproduction

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The pathophysiology of gestational hypertensive disorders is incompletely defined. T lymphocytes are implicated. Both T and natural killer (NK) cells express RAS and, in implantation sites, NK cells are highly enriched. We hypothesized that T cells and/or NK cells contribute to circulatory control during pregnancy. Using radiotelemetry of arterial pressure, heart rate, and activity, mice without T and B cells (genotypes BALB/c-Rag2(-/-) and NOD.scid) were examined at baseline and across pregnancy. These strains differ in NK cell competency, with Rag2(-/-) being normal and NOD.scid impaired. Circulatory features differed between these inbred strains. Rag2(-/-); had blood pressure responses to pregnancy that did not differ from congenic normal mice. NOD.scid had higher midgestational blood pressure compared with normoglycemic NOD mice (3-5 mm Hg greater than NOD; P < 0.004). In comparison to controls, both T and B strains had much higher heart rates after first trimester that did not remit until parturition (>30 bpm greater than control; P < 0.0001). NOD.scid had additional anomalies, including 90% depletion of circulating NK cells and elevated (57%) proliferation of uterine NK cells within implantation sites. These data demonstrate immune control of midgestational heart rate and suggest NK cells contribute to midpregnancy regulation of mean arterial pressure.

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“…Injection of a recombinant adeno-associated viral vector serotype 1 expressing IL-10 into the cerebral artery of rats 3 weeks prior to MCAO results in elevated IL-10 serum levels 3 weeks after injection and decreases neurologic deficit scores, infarct volume, and neuronal injury (49). Systemic IL-10 overexpression in stroke-prone spontaneously hypertensive rats reduces the incidence of stroke, decreases stroke-associated symptoms, and improves survival (50). In Wistar rats, IL-10 is upregulated in viable neurons in the ischemic brain following permanent and transient MCAO, and hypertension blunts this response, potentially contributing to the worse outcomes in the hypertensive setting (41).…”

Section: Ischemic Strokementioning

confidence: 99%

Role of Interleukin-10 in Acute Brain Injuries

et al. 2017

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Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.

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Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat

Cited by 27 publications

References 45 publications

Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

Cardiovascular Adaptations of Pregnancy in T and B Cell-Deficient Mice

Role of Interleukin-10 in Acute Brain Injuries

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