Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension

Dange, Rahul B.; Agarwal, Deepmala; Masson, Gustavo Santos; Vila, Jorge; Wilson, Brad; Nair, Anand; Francis, Joseph

doi:10.1093/cvr/cvu067

Cited by 139 publications

(123 citation statements)

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“…Increased proinflammatory cytokines expression in autonomic control areas, as the PVN, has been identified as a major central molecular mechanism to decrease baroreflex function, to reduce HR variability, and to increase pressure variability and renal sympathetic nerve activity, thus contributing to the development/maintenance of hypertension (7,13,18,38,39). It was also shown that hypertensive rats exhibit elevated proinflammatory cytokines TNF-␣ and IL-6 expression in the PVN (2,31).…”

Section: Discussionmentioning

confidence: 99%

“…Differently from the ANG II-induced hypertension model, which is mostly related to neurogenic drive, SHR exhibits both early autonomic dysfunction (34) and vascular remodeling (3,8). These findings explain the conflicting data: normalization of arterial pressure in ANG II-induced hypertension (7,13,18) and hypertension attenuation in the SHR after chronic blockade of hypothalamic inflammation (14). In previous studies, we also observed partial pressure fall in the SHR submitted to a similar training protocol, which was accompanied by normalization of wall/lumen ratio of skeletal muscle and myocardium arterioles, but only after 4 wk of aerobic exercise training (10,31,32).…”

Section: Discussionmentioning

confidence: 99%

“…Immunofluorescence staining in the PVN was performed as previously reported (2,13,31). Briefly, sequential hypothalamic coronal sections (30 m, Ϫ1.80 to Ϫ2.12 caudal to the bregma, 3 rats/subgroup) were cut with a cryostat (Leica CM 1850; Nussloch, Germany) and collected in tissue culture wells with 0.1 M PB.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, it was demonstrated that acute microinjection of proinflammatory molecules into the PVN of normotensive rats causes elevation of both arterial pressure and renal sympathetic nerve activity (38). On the other hand, chronic inhibition of proinflammatory signaling in the brain decreased arterial pressure and renal sympathetic nerve activity, and reversed the deleterious cardiac remodeling in hypertensive rats (7,13,18,39). Therefore, brain inflammation emerges as a central factor that contributes to autonomic and cardiovascular abnormalities in hypertension.…”

Section: Spontaneously Hypertensive Rats Have Increased Hmgb1 Contentmentioning

confidence: 99%

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Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Masson

Nair

Soares

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Masson GS, Nair AR, Silva Soares PP, Michelini LC, Francis J. Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR. Am J Physiol Heart Circ Physiol 309: H1115-H1122, 2015. First published August 7, 2015; doi:10.1152/ajpheart.00349.2015.-Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IB-␣ phosphorylation, TNF-␣ and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT ϩ SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IB-␣. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control. exercise training; baroreflex; brain inflammation; CXCR4; hypertension NEW & NOTEWORTHY Spontaneously hypertensive rats have increased HMGB1 content and CXCR4 signaling in the hypothalamic paraventricular nucleus, which contributes to microglial activation, proinflammatory cytokines production, and, finally, to autonomic dysfunction. Aerobic training decreases HMGB1 content, microglia activation and proinflammatory cytokines expression by inhibiting HMGB1-CXCR4 signaling pathway in the hypothalamic paraventricular nucleus. Aerobic training induces neuroinflammatory adaptations and autonomic benefits independent of the arterial pressure fall.AUTONOMIC DYSFUNCTION is defined as a misbalance between sympathetic and vagal activity associated with baroreflex dysfunction and increased a...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Spontaneously Hypertensive Rats Have Increased Hmgb1 Contentmentioning

confidence: 99%

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Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Masson

Nair

Soares

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, the molecular targets mediating these actions remain incompletely understood. Because microglia are the major cell types expressing TLR4 within the CNS (38,51,54) and ANG II has been implicated in the induction of the inflammatory response via the TLR4 pathway (17,29,82), we further assessed the contribution of TLR4 to ANG II-induced microglial activation within the PVN.…”

Section: Functional Tlr4 Is Required For Ang Ii-induced Microglial Acmentioning

confidence: 99%

Cross talk between AT₁ receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Biancardi

Stranahan

Krause

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

104

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II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT 1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (ϳ65% increase, P Ͻ 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P Ͻ 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT 1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT 1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN. ANGIOTENSIN II (ANG II) plays a critical role in fluid balance and hemodynamic regulation (25). Within the central nervous system (CNS), ANG II acting through ANG II type 1 a (AT 1a ) receptors (AT 1a R) has been shown to be implicated in the regulation of sympathetic and neuroendocrine outputs from the brain (45, 49, 50). The paraventricular nucleus (PVN) of the hypothalamus has been recognized as a critical neuronal substrate mediating central ANG II actions, thus playing a critical role in ANG II-mediated neurohumoral responses (23, 78). Indeed, a large body of evidence supports enhanced angiotensinergic actions within the CNS, including the PVN, as a key pathophysiological mechanism involved in cardiovascular diseases, including hypertension and heart failure (37,60,78,80,88). However, despite its importance, the precise mechanisms and cellular/ molecular targets underlying ANG II signaling within the CNS are incompletely understood.Inflammation and oxidative stress have emerged as novel mechanisms by which central ANG II mediates its deleterious effects. For example, studies have shown that pressor and sympathetic responses to central ANG II are mediated by superoxide within the PVN (8, 22). Likewise, several studie...

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The Akt pathway mediates the protective effects of myeloid differentiation protein 1 in pathological cardiac remodelling

et al. 2021

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Aims Myeloid differentiation protein 1 (MD1) was shown to ameliorate pressure overload-induced cardiac hypertrophy and fibrosis by negatively regulating the MEK-ERK1/2 and NF-κB pathways. However, whether MD1 modulates cardiac function and whether the Akt pathway mediates the benefits of MD1 in pressure overload-induced cardiac remodelling remain unclear. Methods and Results Male cardiac-specific transgenic MD1 (MD1-TG) mice, MD1-knockout (KO) mice and wild-type (WT) littermates aged 8-10 weeks were subjected to sham operation and aortic banding (AB) for 4 weeks. Then, left ventricular (LV) hypertrophy, fibrosis and function of the mice were assessed. When compared with WT-AB mice, MD1-TGs showed decreased cross-sectional area (CSA) of cardiomyocytes (P < 0.001), mRNA expression of β-myosin heavy chain (β-MHC) (P < 0.02), ratios of heart weight/body weight and heart weight/tibia length (P < 0.04) and collagen volume fraction (P < 0.001). The LV end-diastolic diameter was reduced, and LV ejection fraction and fractional shortening were improved in MD1-TG-AB mice than in WT-AB mice (P < 0.05). In cultured H9C2 cells, adenovirus vector-mediated MD1 overexpression decreased angiotensin II-induced mRNA expression of brain natriuretic peptide (BNP) and β-MHC and cell CSA (P < 0.002), whereas knockdown of MD1 by shRNA exhibited opposite effects (P < 0.04). Mechanistically, MD1 suppressed pathological cardiac remodelling at least partly by blocking Akt pathway. Akt inactivation by MK2206 largely offset the pro-hypertrophic effects of MD1 deficiency in angiotensin II-stimulated cardiomyocytes. Conclusions The Akt pathway mediates the protective effects of MD1 in pressure overload-induced cardiac remodelling in mice. Targeting MD1 may provide therapeutic strategy for the treatment of pathological cardiac remodelling and heart failure.

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Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension

Cited by 139 publications

References 47 publications

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Cross talk between AT₁ receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

The Akt pathway mediates the protective effects of myeloid differentiation protein 1 in pathological cardiac remodelling

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Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension

Cited by 139 publications

References 47 publications

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

The Akt pathway mediates the protective effects of myeloid differentiation protein 1 in pathological cardiac remodelling

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Cross talk between AT₁ receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus