Endoplasmic reticulum stress in bone marrow-derived cells prevents acute cardiac inflammation and injury in response to angiotensin II

Tt, Li; Lx, Jia; Wm, Zhang; Li, XY; Zhang, J; Li, Yali; Hh, Li; Qi, Yuanlin; Du, Jie

doi:10.1038/cddis.2016.164

Cited by 12 publications

(12 citation statements)

References 55 publications

(78 reference statements)

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“…CaMKIIδ-mediated inflammatory gene expression accompanied by macrophage accumulation both occur within 1 day of Ang II treatment, a time point shown here and in the literature to not be associated with death of cardiomyocytes (60). Thus, while CaMKIIδ has been implicated in processes that elicit various forms of cardiomyocyte cell death (61)(62)(63)(64)(65), the modest level of CaMKIIδ activation observed at early times of Ang II infusion serves to elicit inflammatory responses through a rapidly activated transcriptional pathway in cardiomyocytes, rather than through factors released by dying cells.…”

Section: Discussionsupporting

confidence: 63%

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

Willeford¹,

Suetomi²,

Nickle³

et al. 2018

JCI Insight

106

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Inflammation accompanies heart failure and is a mediator of cardiac fibrosis. CaMKIIδ plays an essential role in adverse remodeling and decompensation to heart failure. We postulated that inflammation is the mechanism by which CaMKIIδ contributes to adverse remodeling in response to nonischemic interventions. We demonstrate that deletion of CaMKIIδ in the cardiomyocyte (CKO) significantly attenuates activation of NF-κB, expression of inflammatory chemokines and cytokines, and macrophage accumulation induced by angiotensin II (Ang II) infusion. The inflammasome was activated by Ang II, and this response was also diminished in CKO mice. These events occurred prior to any evidence of Ang II-induced cell death. In addition, CaMKII-dependent inflammatory gene expression and inflammasome priming were observed as early as the third hour of infusion, a time point at which macrophage recruitment was not evident. Inhibition of either the inflammasome or monocyte chemoattractant protein 1 (MCP1) signaling attenuated macrophage accumulation, and these interventions, like cardiomyocyte CaMKIIδ deletion, diminished the fibrotic response to Ang II. Thus, activation of CaMKIIδ in the cardiomyocyte represents what we believe to be a novel mechanism for initiating inflammasome activation and an inflammatory gene program that leads to macrophage recruitment and ultimately to development of fibrosis.

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Section: Discussionsupporting

confidence: 63%

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

Willeford¹,

Suetomi²,

Nickle³

et al. 2018

JCI Insight

106

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“…4,51,52 However, the precise inflammatory pathways which are induced by Ang II are not well established yet in beta cells as well in other tissues. 53,54 Our study and others have demonstrated that activation of RAAS could contribute to inflammation. 21 Furthermore, increased Chop expression, an ER stress marker, induced inflammation through the NFkB pathway.…”

Section: Dovepressmentioning

confidence: 64%

<p>Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells</p>

Ramalingam¹,

Sopontammarak²,

Menikdiwela³

et al. 2020

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Introduction: The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion. Methods: To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors. Results: We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion. Discussion: This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.

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“…Thus inflammation is a key mediator of AngII-induced beta cell dysfunction (11). A role for ER stress in AngII-mediated inflammation has recently been shown in other cell types/tissues (41)(42)(43), yet the mechanism by which this occurs had not been fully explored.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Causes β-Cell Dysfunction Through an ER Stress-Induced Proinflammatory Response

et al. 2017

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The metabolic syndrome is associated with an increase in the activation of the renin angiotensin system, whose inhibition reduces the incidence of new-onset diabetes. Importantly, angiotensin II (AngII), independently of its vasoconstrictor action, causes β-cell inflammation and dysfunction, which may be an early step in the development of type 2 diabetes. The aim of this study was to determine how AngII causes β-cell dysfunction. Islets of Langerhans were isolated from C57BL/6J mice that had been infused with AngII in the presence or absence of taurine-conjugated ursodeoxycholic acid (TUDCA) and effects on endoplasmic reticulum (ER) stress, inflammation, and β-cell function determined. The mechanism of action of AngII was further investigated using isolated murine islets and clonal β cells. We show that AngII triggers ER stress, an increase in the messenger RNA expression of proinflammatory cytokines, and promotes β-cell dysfunction in murine islets of Langerhans both in vivo and ex vivo. These effects were significantly attenuated by TUDCA, an inhibitor of ER stress. We also show that AngII-induced ER stress is required for the increased expression of proinflammatory cytokines and is caused by reactive oxygen species and IP3 receptor activation. These data reveal that the induction of ER stress is critical for AngII-induced β-cell dysfunction and indicates how therapies that promote ER homeostasis may be beneficial in the prevention of type 2 diabetes.

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Endoplasmic reticulum stress in bone marrow-derived cells prevents acute cardiac inflammation and injury in response to angiotensin II

Cited by 12 publications

References 55 publications

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

<p>Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells</p>

Angiotensin II Causes β-Cell Dysfunction Through an ER Stress-Induced Proinflammatory Response

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