Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

Sweeney, Mark; Corden, Ben; Cook, Stuart A.

doi:10.15252/emmm.201910865

Cited by 110 publications

(80 citation statements)

References 364 publications

(427 reference statements)

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“…Cardiac fibroblasts are well known to play critical roles in the pathogenesis of diabetic cardiac fibrosis 24 , 25 . The effect of KLK8 on cardiac fibroblasts was next evaluated.…”

Section: Resultsmentioning

confidence: 99%

A novel role of kallikrein-related peptidase 8 in the pathogenesis of diabetic cardiac fibrosis

Du¹,

Yu²,

Liu³

et al. 2021

Theranostics

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Rationale: Among all the diabetic complications, diabetic cardiomyopathy, which is characterized by myocyte loss and myocardial fibrosis, is the leading cause of mortality and morbidity in diabetic patients. Tissue kallikrein-related peptidases (KLKs) are secreted serine proteases, that have distinct and overlapping roles in the pathogenesis of cardiovascular diseases. However, whether KLKs are involved in the development of diabetic cardiomyopathy remains unknown.The present study aimed to determine the role of a specific KLK in the initiation of endothelial-to-mesenchymal transition (EndMT) during the pathogenesis of diabetic cardiomyopathy. Methods and Results- By screening gene expression profiles of KLKs, it was found that KLK8 was highly induced in the myocardium of mice with streptozotocin-induced diabetes. KLK8 deficiency attenuated diabetic cardiac fibrosis, and rescued the impaired cardiac function in diabetic mice. Small interfering RNA (siRNA)-mediated KLK8 knockdown significantly attenuated high glucose-induced endothelial damage and EndMT in human coronary artery endothelial cells (HCAECs). Diabetes-induced endothelial injury and cardiac EndMT were significantly alleviated in KLK8-deficient mice. In addition, transgenic overexpression of KLK8 led to interstitial and perivascular cardiac fibrosis, endothelial injury and EndMT in the heart. Adenovirus-mediated overexpression of KLK8 (Ad-KLK8) resulted in increases in endothelial cell damage, permeability and transforming growth factor (TGF)-β1 release in HCAECs. KLK8 overexpression also induced EndMT in HCAECs, which was alleviated by a TGF-β1-neutralizing antibody. A specificity protein-1 (Sp-1) consensus site was identified in the human KLK8 promoter and was found to mediate the high glucose-induced KLK8 expression. Mechanistically, it was identified that the vascular endothelial (VE)-cadherin/plakoglobin complex may associate with KLK8 in HCAECs. KLK8 cleaved the VE-cadherin extracellular domain, thus promoting plakoglobin nuclear translocation. Plakoglobin was required for KLK8-induced EndMT by cooperating with p53. KLK8 overexpression led to plakoglobin-dependent association of p53 with hypoxia inducible factor (HIF)-1α, which further enhanced the transactivation effect of HIF-1α on the TGF-β1 promoter. KLK8 also induced the binding of p53 with Smad3, subsequently promoting pro-EndMT reprogramming via the TGF-β1/Smad signaling pathway in HCAECs. The in vitro and in vivo findings further demonstrated that high glucose may promote plakoglobin-dependent cooperation of p53 with HIF-1α and Smad3, subsequently increasing the expression of TGF-β1 and the pro-EndMT target genes of the TGF-β1/Smad signaling pathway in a KLK8-dependent manner. Conclusions: The present findings uncovered a novel pro-EndMT mechanism during the pathogenesis of diabetic cardiac fibrosis via the upregulation of KLK8, and may contribute to the development of future KL...

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“…Cardiac fibroblasts are well known to play critical roles in the pathogenesis of diabetic cardiac fibrosis 24 , 25 . The effect of KLK8 on cardiac fibroblasts was next evaluated.…”

Section: Resultsmentioning

confidence: 99%

A novel role of kallikrein-related peptidase 8 in the pathogenesis of diabetic cardiac fibrosis

Du¹,

Yu²,

Liu³

et al. 2021

Theranostics

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“…We also showed that through lentivirus, this expression vector can be delivered to animals for potential treatment of tissue fibrosis. It is well established that TGF-β pathway is a potent activator of profibrotic effects in cells and has been described as the “master regulators” of fibrosis [ 3 , 33 ]. A variety of strategies have been developed to target the TGF-β signaling, including TGF-β receptor inhibitors [ 34 ] and monoclonal antibody against TGF-β [ 35 ].…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…A variety of strategies have been developed to target the TGF-β signaling, including TGF-β receptor inhibitors [ 34 ] and monoclonal antibody against TGF-β [ 35 ]. However, due to its importance in normal cells, the therapeutic methods that totally block the TGF-β pathway have been shown to cause significant cardiovascular toxicity [ 3 ], which include inflammatory infiltration in blood vessels and heart valves [ 36 ] and degeneration of heart valve [ 37 ]. Our work showed a possibility of strategically inhibiting downstream of TGF-β pathway by a sensor mechanism, which up-regulates the anti-fibrotic molecules in response to fibrotic stimulation.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…Formation of tissue fibrosis is a driving force for disease progression that leads to worsened organ function and failure [ 1 , 2 ]. Cardiac fibrosis plays an important role in etiology of almost all forms of heart failure and particularly in heart failure with preserved ejection fraction [ 3 , 4 ]. Myocardial infarction (MI) is a major cause of cardiac death and massive cardiac tissue fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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A strategic expression method of miR-29b and its anti-fibrotic effect based on RNA-sequencing analysis

et al. 2020

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Tissue fibrosis is a significant health issue associated with organ dysfunction and failure. Increased deposition of collagen and other extracellular matrix (ECM) proteins in the interstitial area is a major process in tissue fibrosis. The microRNA-29 (miR-29) family has been demonstrated as anti-fibrotic microRNAs. Our recent work showed that dysregulation of miR-29 contributes to the formation of cardiac fibrosis in animal models of uremic cardiomyopathy, whereas replenishing miR-29 attenuated cardiac fibrosis in these animals. However, excessive overexpression of miR-29 is a concern because microRNAs usually have multiple targets, which could result in unknown and unexpected side effect. In the current study, we constructed a novel Col1a1-miR-29b vector using collagen 1a1 (Col1a1) promoter, which can strategically express miR-29b-3p (miR-29b) in response to increased collagen synthesis and reach a dynamic balance between collagen and miR-29b. Our experimental results showed that in mouse embryonic fibroblasts (MEF cells) transfected with Col1a1-miR-29b vector, the miR-29b expression is about 1000 times less than that in cells transfected with CMV-miR-29b vector, which uses cytomegalovirus (CMV) as a promoter for miR-29b expression. Moreover, TGF-β treatment increased the miR-29b expression by about 20 times in cells transfected with Col1a1-miR-29b, suggesting a dynamic response to fibrotic stimulation. Western blot using cell lysates and culture media demonstrated that transfection of Col1a1-miR-29b vector significantly reduced TGF-β induced collagen synthesis and secretion, and the effect was as effective as the CMV-miR-29b vector. Using RNA-sequencing analysis, we found that 249 genes were significantly altered (180 upregulated and 69 downregulated, at least 2-fold change and adjusted p-value <0.05) after TGF-β treatment in MEF cells transfected with empty vector. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using GAGE R-package showed that the top 5 upregulated pathways after TGF-β treatment were mostly fibrosis-related, including focal adhesion, ECM reaction, and TGF-β signaling pathways. As expected, transfection of Col1a1-miR-29b or CMV-miR-29b vector partially reversed the activation of these pathways. We also analyzed the expression pattern of the top 100 miR-29b targeting genes in these cells using the RNA-sequencing data. We identified that miR-29b targeted a broad spectrum of ECM genes, but the inhibition effect is mostly moderate. In summary, our work demonstrated that the Col1a1-miR-29b vector can be used as a dynamic regulator of collagen and other ECM protein expression in response to fibrotic stimulation, which could potentially reduce unnecessary side effect due to excessive miR-29b levels while remaining an effective potential therapeutic approach for fibrosis.

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“…Furthermore, massive clinical and experimental data have demonstrated that chronic activation of cardiac fibroblasts (CFs) and accumulation of cardiac fibrosis adversely affect cardiac compliance, cause diastolic dysfunction (2, 3), and leads to arrhythmia and sudden death (4, 5). Even though cardiac fibrosis is clinically important in HF, effective anti-fibrosis therapeutics are not available till date (6, 7). Therefore, understanding the underpinning mechanisms of cardiac fibrosis and identifying novel modalities to modulate this process are of high scientific impact and therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

FAM114A1 Influences Cardiac Fibrosis by Regulating Angiotensin II Signaling in Cardiac Fibroblasts

Subbaiah

Tang

et al. 2021

Preprint

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Cardiac fibrosis, a primary contributor to heart failure (HF) and sudden death, is considered as an important target for HF therapy. However, the signaling pathways that govern cardiac fibroblast (CF) function during cardiac fibrosis have not been fully elucidated. Here, we found that a functionally unannotated human myocardial infarction (MI) associated gene, family with sequence similarity 114 member A1 (FAM114A1), is induced in failing human and mouse hearts compared to non-failing hearts. Homozygous knockout of Fam114a1 (Fam114a1-/-) in the mouse genome reduces cardiac hypertrophy and fibrosis while significantly restores cardiac function in angiotensin (Ang) II- and MI-induced HF mouse models. Fam114a1 deletion antagonizes Ang II induced inflammation and oxidative stress. Using isolated mouse primary CFs in wild type and Fam114a1-/- mice, we found that FAM114A1 is a critical autonomous factor for CF proliferation, activation, and migration. We discovered that FAM114A1 interacts with angiotensin receptor associated protein (AGTRAP) and regulates the expression of angiotensin type 1 receptor (AT1R) and downstream Ang II signaling transduction, and subsequently influences pro-fibrotic response. Using RNA-Seq in mouse primary CFs, we identified differentially expressed genes including extracellular matrix proteins such as Adamts15. RNAi-mediated inactivation of Adamts15 attenuates CF activation and collagen deposition. Our results indicate that FAM114A1 regulates Ang II signaling and downstream pro-fibrotic and pro-inflammatory gene expression, thereby activating cardiac fibroblasts and augmenting pathological cardiac remodeling. These findings provide novel insights into regulation of cardiac fibrosis and identify FAM114A1 as a new therapeutic target for treatment of cardiac disease.

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Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

Cited by 110 publications

References 364 publications

A novel role of kallikrein-related peptidase 8 in the pathogenesis of diabetic cardiac fibrosis

A novel role of kallikrein-related peptidase 8 in the pathogenesis of diabetic cardiac fibrosis

A strategic expression method of miR-29b and its anti-fibrotic effect based on RNA-sequencing analysis

FAM114A1 Influences Cardiac Fibrosis by Regulating Angiotensin II Signaling in Cardiac Fibroblasts

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