Cardiac c-kit+AT2+ Cell Population is Increased in Response to Ischemic Injury and Supports Cardiomyocyte Performance

Altarche-Xifró, Wassim; Curato, Caterina; Kaschina, Elena; Grzesiak, Aleksandra; Slavić, Svetlana; Dong, Jun; Kappert, Kai; Steckelings, Ulrike Muscha; Imboden, Hans; Unger, Thomas; Li, Jun

doi:10.1002/stem.171

Cited by 61 publications

(67 citation statements)

References 37 publications

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“…Most of the actions of Ang II, including blood pressure and osmotic control, are mediated by AT1Rs (6). In contrast, the upregulation of AT2R, which occurs during acute tissue injury, including MI (8,16) and brain ischemia (17), speaks in favor of its potential role in the early cellular response to tissue injury. At the cellular level, we have previously shown that the number of AT2R-expressing CMs was not changed after acute MI, suggesting that noncardiomyocytes may account for the upregulated AT2R in the infarcted heart (16).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, debatable observations on AT2R expression in cardiac fibroblasts of patients with heart failure argue whether AT2R is involved in the regulation of cardiac fibrotic process (7). Our recent data show that cardiac c-Kit + AT2R + cell population exists and concerns adaptive cardioprotection (8), raising the importance of other potential cellular mechanisms, which may also contribute to AT2R-mediated repair processes in the heart. Several previous studies have suggested that Ang II via its AT1R plays an important role in triggering inflammatory cardiovascular injury (4,5).…”

mentioning

confidence: 86%

“…Apoptotic CM was examined by an ethidium bromide/acridine orange method (8). A minimum of n = 100 CMs/well was counted.…”

Section: Determination Of Apoptotic Cms In Vitromentioning

confidence: 99%

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Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

Curato

Slavić

Dong

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 86%

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Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

Curato

Slavić

Dong

et al. 2010

The Journal of Immunology

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“…There is evidence that an interesting link exists between CD117 + SC function and the renin-angiotensin system (RAS), which interferes with inflammation and acute cardiac remodeling processes during cardiac injury [21]. Thereby, the angiotensin II type-2 receptor (AT2R) by mediating actions of the active metabolite Angiotensin II (Ang II), opposes effects of the angiotensin II type-1 receptor (AT1R) [22,23].…”

Section: Introductionmentioning

confidence: 99%

Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

Ludwig¹,

Tölk²,

Skorska³

et al. 2015

Cell Physiol Biochem

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Background/Aims: CD117⁺ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117⁺ SC implantation. In particular, the link between CD117⁺ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117⁺ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117⁺ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117⁺ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117⁺ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.

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“…Other findings suggest that C21 can improve heart health in even more ways. In human cardiac stem cells, for example, stimulating the AT 2 receptors slows the death of heart muscle cells 6 . Likewise, activating AT 2 receptors bound to immune cells in specific parts of the heart makes these cells fight inflammation, thereby protecting the heart 7 .…”

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confidence: 99%

Perspective: A tale of two receptors

Foulquier

Steckelings

Unger³

2013

Nature

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OUTLOOK HEART HEALTH I magine someone cut severely in an accident and losing blood fast. Blood pressure drops dangerously low as blood is lost, and the kidneys react by releasing the enzyme renin. The circulating renin leads to the production of angiotensin II, a hormone that constricts blood vessels and prompts the kidneys to retain more salt and water to prop up the blood pressure. This renin-angiotensin system can save the life of our imagined person as they lay bleeding to death. Under other circumstances, it can kill. Our research reveals that the renin-angiotensin system might be tweaked in novel ways to fight heart disease -but we can only do that accurately and precisely by first learning the exact details of how the system's hormone receptors work.The consequences of activating the renin-angiotensin system depend on the circumstances, and to which receptor the angiotensin II binds. If it binds to the angiotensin AT 1 receptor, the blood pressure-increasing mechanism is engaged. And AT 1 receptor binding under normal circumstances can raise blood pressure and damage the cells of the heart's left ventricle, the chamber that pumps oxygenated blood out of the heart. In addition, clinical studies have shown that drugs that block this receptor can also reduce damage to the heart. Therefore, blocking this receptor serves as a therapeutic strategy for treating cardiovascular diseases, especially hypertension.When drugs for high blood pressure block a receptor docking site for angiotensin II, more of the hormone remains free to circulate in the blood. Increased levels of circulating angiotensin II affect a second receptor, AT 2 . The AT 2 receptor triggers a molecular cascade that expands the size of blood vessels and helps prevent damage to the heart. In essence, the actions triggered by the second receptor are the opposite of the processes caused by the first. In addition, the body makes more AT 2 receptors in response to several pathological conditions, including heart attack, heart failure and stroke. So when things go wrong with the cardiac system, the AT 2 receptor system appears to serve a protective function.Other research results support such a protective role for the AT 2 receptor. In one study, for example, researchers engineered animals with varying amounts of AT 2 receptor and confirmed that it can activate mechanisms that protect the heart 1 (some studies produced conflicting results, possibly due to different receptor production levels in the genetically altered animals). As well as modifying the amount of the receptor, researchers can look for molecules other than angiotensin II that can turn on the AT 2 receptor. Just such a molecule exists, and it's called compound 21 (C21).We and other research groups have tested C21's ability to influence high blood pressure, but surprisingly C21 has no effect on the condition 2 . Nonetheless, our results continue to suggest the potential of exploiting this compound's role in repairing an injured heart. For example, C21 reduces stiffness in arteries, an effec...

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Cardiac c-kit+AT2+ Cell Population is Increased in Response to Ischemic Injury and Supports Cardiomyocyte Performance

Cited by 61 publications

References 37 publications

Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

Perspective: A tale of two receptors

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