Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Kamo, Takehiro; Akazawa, Hiroshi; Komuro, Issei

doi:10.1161/circresaha.117.305349

Cited by 130 publications

(100 citation statements)

References 121 publications

(136 reference statements)

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“…In addition, they also produce and secrete growth factors, cytokines, and other signalling molecules (such as IL-1β, IL-6, and tumour necrosis factor (TNF)-α; reviewed in [6, 86, 87]). Recent reports have shown that another facet of fibroblast paracrine signalling is based on microvesicle (exosome) secretion by fibroblasts and subsequent cardiomyocyte uptake of these vesicles.…”

Section: The Many Roles Of Scar Fibroblastsmentioning

confidence: 99%

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Rog-Zielinska

Norris

Kohl

et al. 2016

Trends in Molecular Medicine

131

102

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Cardiac scars, often perceived as “dead” tissue, are very much alive, with heterocellular activity ensuring the maintenance of structural and mechanical integrity following heart injury. To form a scar, non-myocytes such as fibroblasts, proliferate and are recruited from intra- and extra-cardiac sources. Fibroblasts perform important autocrine and paracrine signalling functions. They also establish mechanical and, as is increasingly evident, electrical junctions with other cells. While fibroblasts were previously thought to act simply as electrical insulators, they may be electrically connected among themselves and, under certain circumstances, to other cells, including cardiomyocytes. A better understanding of these interactions will help target scar structure and function and facilitate the development of novel therapies aimed at modifying scar properties for patient benefit. This review explores available insight and recent concepts on fibroblast integration in the heart, and highlights potential avenues for harnessing their roles to optimise scar function following heart injury such as infarction, and therapeutic interventions such as ablation.

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Section: The Many Roles Of Scar Fibroblastsmentioning

confidence: 99%

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Rog-Zielinska

Norris

Kohl

et al. 2016

Trends in Molecular Medicine

131

102

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“…5 These findings, however, are at odds with those of a seminal study involving a murine renal cross-transplantation model, which reported a critical role for increased blood pressure resulting from activation of the kidney Ang II type-1 receptor in cardiac remodeling in response to Ang II treatment. 6 Graft-driven inflammation does not occur in this model, but given recent evidence that the immune system is important in cardiovascular remodeling, 7 one may speculate that immunotolerance may have been induced and affected the outcome.…”

Section: See Related Article Pp 949-955mentioning

confidence: 94%

“…7 For instance, endothelial-specific deletion of interleukin-33 was recently reported to worsen transverse aortic constriction-induced cardiac hypertrophy. 8 Finally, the study by Takayanagi et al 2 does not definitively establish the causative factor in hypertension-induced cardiac remodeling, which is assumed to be heparin-binding EGF-like growth factor.…”

Section: Hypertensionmentioning

confidence: 99%

“…Their observation is consistent with the findings made with other models of hypertension-induced cardiac hypertrophy. For instance, Ang II type-1 receptor blockade attenuated cardiac hypertrophy in response to transverse aortic constriction, 4 and knockdown of ADAM17 with siRNA attenuated cardiac hypertrophy in the spontaneously hypertensive rat without diminishing blood pressure.5 These findings, however, are at odds with those of a seminal study involving a murine renal cross-transplantation model, which reported a critical role for increased blood pressure resulting from activation of the kidney Ang II type-1 receptor in cardiac remodeling in response to Ang II treatment.6 Graft-driven inflammation does not occur in this model, but given recent evidence that the immune system is important in cardiovascular remodeling, 7 one may speculate that immunotolerance may have been induced and affected the outcome.The study by Takayanagi et al 2 is also remarkable because it raises the possibility that vascular remodeling may actually drive or at least make a substantial contribution to cardiac remodeling. Although vascular smooth muscle cell-dominant deletion of ADAM17 was achieved by sm22α promoter-driven Cre expression, the possibility that ADAM17 was effectively deleted in cardiac myocytes as well, because of their moderate and transient embryonic expression of sm22α, precludes a definitive conclusion in this regard.…”

mentioning

confidence: 91%

“…6 Graft-driven inflammation does not occur in this model, but given recent evidence that the immune system is important in cardiovascular remodeling, 7 one may speculate that immunotolerance may have been induced and affected the outcome.…”

mentioning

confidence: 95%

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Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy

Altara

Booz

2016

Hypertension

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A disintegrin and metalloprotease (ADAM) 17 has sheddase activity for cleaving the ectodomain of several precursor molecules, including heparin-binding epidermal growth factor (EGF)-like growth factor. Over the past decade, Dr Eguchi and his colleagues have meticulously presented evidence that ADAM17 couples the angiotensin II (Ang II) type-1 (AT1) receptor to activation of the EGF receptor (EGFR) in vascular smooth muscle cells. Studies on cultured cells have shown that EGFR transactivation is responsible for vascular smooth muscle cell hypertrophy in response to Ang II, but not contractility. Moreover, EGF was found to be capable of inducing endoplasmic reticulum stress, which serves to enhance the coupling of Ang II to EGFR signaling by upregulating the expression of ADAM17. In a study that appeared last year in Hypertension, Eguchi's group reported that inhibiting EGFR or endoplasmic reticulum stress attenuated vascular remodeling and cardiac hypertrophy in mice infused with Ang II, without affecting the increase in blood pressure. 1 In the current issue, these investigators extend these observations further by showing that knockout of ADAM17 specifically in vascular smooth muscle cells prevents cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis in mice treated with Ang II, again without affecting the induced hypertension.2 ADAM17 deficiency also diminished EGFR activation and endoplasmic reticulum stress in the vasculature, and a similar outcome was achieved by treatment of Ang II-infused mice with a human cross-reactive ADAM17 inhibitory antibody ( Figure).These new findings are remarkable for several reasons. First, they provide additional support for the contention that increased blood pressure and adverse cardiovascular remodeling, which contributes to end-organ damage, are independent phenomena that can be targeted separately. This conclusion has profound clinical significance given that hypertension for many individuals is difficult to control with current drugs and strategies. Moreover, as mentioned by Takayanagi et al, 2 optimally treated hypertensive patients are at an increased risk of a cardiovascular event compared with untreated normotensive subjects. Thus, there is a great need to identify druggable targets to prevent the complications of hypertension, and ADAM17 may represent such a target.Left ventricular hypertrophy represents a stronger risk factor than increased blood pressure for adverse cardiovascular events, and accumulating evidence indicates that elevated blood pressure and cardiac hypertrophy can be targeted independently. Odenbach et al 3 reported evidence that it is possible to block hypertension and still observe cardiac hypertrophy and fibrosis in the Ang II-infused mouse by targeting matrix metalloproteinase 2 (MMP-2), which was placed downstream of MMP-7 and ADAM17 activation. MMP-7 and ADAM17 were linked to both hypertension and cardiac remodeling by independent mechanisms. Simultaneously knocking down MMP-7 and ADAM17 with siRNA attenuated both Ang I...

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Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation

Maaten

Damman

Verhaar

et al. 2016

European J of Heart Fail

256

191

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Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

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Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Cited by 130 publications

References 121 publications

The Living Scar – Cardiac Fibroblasts and the Injured Heart

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy

Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation

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