Immune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling

Frieler, Ryan A.; Mortensen, Richard M.

doi:10.1161/circulationaha.114.008788

Cited by 296 publications

(272 citation statements)

References 105 publications

(105 reference statements)

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“…What is more, cardiomyocytes from ablated hearts expressed higher levels of messenger RNA for hypertrophic growth factor transforming growth factor β1 (TGFβ1) and showed a trend to increased interleukin-6 production ( Figure 6D). Because also immune cells importantly contribute to the remodeling process, [26][27][28] we extended our analysis to cardiac macrophages, here identified by the expression of Integrin α M (CD11b). Also, these cells showed significantly increased expression of genes encoding prohypertrophic factors such as TGFβ1 and platelet-derived growth factor B (PDGF-B), as well as trends to increased expression of genes encoding PDGF-A and TGFβ2 ( Figure 6E).…”

Section: β-Galmentioning

confidence: 99%

Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

Kaur

Takefuji

Ngai

et al. 2016

Circulation Research

212

178

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Rationale: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear. Objective: To study the effect of CF ablation on cardiac remodeling. Methods and Results: We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome–transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy. Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

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Section: β-Galmentioning

confidence: 99%

Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

Kaur

Takefuji

Ngai

et al. 2016

Circulation Research

212

178

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“…20,21 Previous reports showed that various inflammatory cytokines participate in the progression of maladaptive cardiac remodeling during pressure overload. 22 Notably, MCP-1 reportedly contributes to adverse cardiac remodeling in response to pressure overload and ischemic stimuli in animal models. [23][24][25] Therefore, we investigated whether MCP-1 was expressed in the hypertrophied hearts of the sFlt1 −/− mice.…”

Section: Upregulation Of Mcp-1 Expression Contributes To the Progressmentioning

confidence: 99%

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure

et al. 2016

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Abstract-Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart. Correspondence to Yoshihiko Saito, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. E-mail saitonaramed@gmail.com Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to MyocardialRemodeling and Heart Failure Ayako Seno, Yukiji Takeda, Masaru Matsui, Aya Okuda, Tomoya Nakano, Yasuki Nakada, Takuya Kumazawa, Hitoshi Nakagawa, Taku Nishida, Kenji Onoue, Satoshi Somekawa, Makoto Watanabe, Hiroyuki Kawata, Rika Kawakami, Hiroyuki Okura, Shiro Uemura, Yoshihiko Saito © 2016 American Heart Association, Inc. function in patients with acute coronary syndrome. 6 Therefore, it seems that insufficient sFlt-1 production is associated with adverse cardiovascular outcomes.On the contrary, several previous reports have shown that upregulation of sFlt-1 contributes to the development of heart failure, with antiangiogenesis activity by binding to VEGF. 7,8 In clinical settings, plasma levels of sFlt-1 are not only directly correlated with the severity of heart failure but also strongly associated with poor outcomes in patients with heart failure.9,10 These observations provide a plausible interpretation that increased sFlt-1 production aggravates heart failure with adverse car...

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“…The process involves cardiomyocyte lengthening and thinning of the infarct zone followed by inflammation and immune cell activation. Numerous cell types are involved in orchestrating this complex pathological response, as the heart consists of a heterogeneous population of cells, including cardiomyocytes, interstitial cells, connective tissue cells, smooth muscle cells, endothelial cells and other non-cardiomyocytes [9]. As a result, there is inflammatory and immunological activation, and the initiation of a repairing action, which will eventually cause re-absorption of necrotic tissue and stimulate production of interstitial collagen, leading to scar formation [14].…”

Section: Remodelling After Myocardial Infarctionmentioning

confidence: 99%

“…If the molecular secrets of remodelling could be unlocked, more specific interventions to induce full cardiac repair and recovery might result. The scientific literature provides many reviews describing the molecular changes involved in remodelling, with some recently published [7,8,9,10,11,12]. This, however, is not the scope of our article.…”

Section: Introductionmentioning

confidence: 99%

Remodelling after an Infarct: Crosstalk between Life and Death

et al. 2016

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Immune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling

Cited by 296 publications

References 105 publications

Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure

Remodelling after an Infarct: Crosstalk between Life and Death

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