Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure

Weber, Karl T.; Dı́ez, Javier

doi:10.1161/circheartfailure.116.003315

Cited by 20 publications

(18 citation statements)

References 20 publications

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“…The counter regulatory role of ACE2 on the maladaptive effects of ACE and AT2(1-8) make ACE2 and its related APs attractive targets for pharmacotherapy. 23,[25][26][27]45,[59][60][61] Treatment with exogenous ACE2 is particularly interesting in light of the fact that the affinity of ACE2 to cleave AT2…”

Section: Discussionmentioning

confidence: 99%

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

Larouche‐Lebel

Loughran

Oyama

et al. 2019

Veterinary Internal Medicne

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Background Angiotensin‐converting enzyme 2 (ACE2) is a homologue of angiotensin‐converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1‐9 and 1‐7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. Hypothesis Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. Animals Forty‐nine dogs with and 34 dogs without heart disease. Methods Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. Results Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1‐12.1) as compared to control (2.2 mU/mg; IQR, 1.8‐3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1‐7, in dogs with CHF (486.7 pg/mL; IQR, 214.2‐1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4‐45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1‐25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1‐9 (preincubation, 10.3 pg/mL; IQR, 4.4‐37.2; postincubation, 2431 pg/mL; IQR, 1355‐3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6‐226.4; postincubation, 2.4 pg/mL; IQR, 0.50‐5.8; P = .02). Conclusions and Clinical Importance Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

Larouche‐Lebel

Loughran

Oyama

et al. 2019

Veterinary Internal Medicne

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“…Pronounced pathological dissemination of myofibroblasts and adverse fibrosis have been associated to changes in fibroblast secretory profiles 8,11 . Thus, we screened for common differentially regulated pathways and upstream regulators between all secretomes to determine possible factors that could be responsible for the orchestration of Rhein-mediated effects.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, chronic or prolonged periods of hypoxia have been hypothesized to be involved in adverse fibrosis, directly associated to changes of fibroblast behavior and modulation of secreted soluble factors i.e. VEGF or TGFβ by CFs 8,11,12 . Thus, the local intercellular crosstalk through different secretion profiles constitutes a possible driving mechanism in the propagation of MFs throughout the heart and for maladapted remodeling.…”

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confidence: 99%

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Rhein, a novel Histone Deacetylase (HDAC) inhibitor with antifibrotic potency in human myocardial fibrosis

Barbosa

Fahlbusch

Wiza

et al. 2020

Sci Rep

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Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as antifibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.

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“…The early phase of DCM is characterized by symptoms of diastolic heart failure, which is caused by myocardial fibrosis via excess fibrotic processes, even without the loss of cardiomyocytes (with preserved left ventricular systolic function) [ 7 , 8 , 9 ]. Myocardial fibrosis is a hallmark of heart disease, and is defined as an abnormal deposition of collagen, fibronectin, and other extracellular matrices, which leads to increased myocardial stiffness and consequent cardiac dysfunction, ultimately resulting in heart failure [ 10 , 11 , 12 , 13 ]. Streptozotocin (STZ)-induced diabetic mice with impaired diastolic function, heart failure, and exhibiting features of cardiac hypertrophy, myofibril depletion, and interstitial fibrosis were developed, and are used to study the mechanism of DCM [ 6 , 7 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress

Tsai

Lin

Chua

et al. 2018

IJMS

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Background: Diabetic cardiomyopathy (DCM) is characterized by cardiac fibrosis and stiffness, which often develops into heart failure. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. Methods: Forty-eight mice were divided into four groups (n = 12 per group): Group 1: Wild-type (WT) mice, Group 2: RasGRF1 deficiency (RasGRF1−/−) mice. Group 3: Streptozotocin (STZ)-induced diabetic WT mice, Group 4: STZ-induced diabetic RasGRF1−/− mice. Myocardial functions were assessed by cardiac echography. Heart tissues from all of the mice were investigated for cardiac fibrosis, inflammation, and oxidative stress markers. Results: Worse impaired diastolic function with elevation serum interleukin (IL)-6 was found in the diabetic group compared with the non-diabetic groups. Serum IL-6 levels were found to be elevated in the diabetic compared with the non-diabetic groups. However, the diabetic RasGRF1−/− mice exhibited lower serum IL-6 levels and better diastolic function than the diabetic WT mice. The diabetic RasGRF1−/− mice were associated with reduced cardiac inflammation, which was shown by lower invading inflammation cells, lower expression of matrix metalloproteinase 9, and less chemokines compared to the diabetic WT mice. Furthermore, less oxidative stress as well as extracellular matrix deposition leading to a reduction in cardiac fibrosis was also found in the diabetic RasGRF1−/− mice compared with the diabetic WT mice. Conclusion: The deletion of RasGRF1 attenuated myocardial fibrosis and improved cardiac function in diabetic mice through inhibiting inflammation and oxidative stress.

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Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure

Cited by 20 publications

References 20 publications

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

Rhein, a novel Histone Deacetylase (HDAC) inhibitor with antifibrotic potency in human myocardial fibrosis

Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress

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