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Reversion inducing cysteine rich protein with Kazal motifs and cardiovascular diseases: The RECKlessness of adverse remodeling.

ABSTRACT: The Reversion Inducing Cysteine Rich Protein With Kazal Motifs (RECK) is a glycosylphosphatidylinositol (GPI) anchored membrane-bound regulator of matrix metalloproteinases (MMPs). It is expressed throughout the body and plays a role in extracellular matrix (ECM) homeostasis and inflammation. In initial studies, RECK expression was found to be downregulated in various invasive cancers and associated with poor prognostic outcome. Restoring RECK, however, has been shown to reverse the metastatic phenotype. Downregulation of RECK expression is also reported in non-malignant diseases, such as periodontal disease, renal fibrosis, and myocardial fibrosis. As such, RECK induction has therapeutic potential in several chronic diseases. Mechanistically, RECK negatively regulates various matrixins involved in cell migration, proliferation, and adverse remodeling by targeting the expression and/or activation of multiple MMPs, A Disintegrin And Metalloproteinase Domain-Containing Proteins (ADAMs), and A Disintegrin And Metalloproteinase With Thrombospondin Motifs (ADAMTS). Outside of its role in remodeling, RECK has also been reported to exert anti-inflammatory effects. In cardiac diseases, for example, it has been shown to counteract several downstream effectors of Angiotensin II (Ang-II) that play a role in adverse cardiac and vascular remodeling, such as Interleukin-6 (IL-6)/IL-6 receptor (IL-6R)/glycoprotein 130 (IL-6 signal transducer) signaling and Epidermal Growth Factor Receptor (EGFR) transactivation. This review article focuses on the current understanding of the multifunctional effects of RECK and how its downregulation may contribute to adverse cardiovascular remodeling.

SUBMITTER: Russell JJ

PROVIDER: S-EPMC8204737 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Significance The findings to date indicate that adverse childhood experiences (ACEs) increase the risk of cardiovascular disease (CVD) in later life. We demonstrate how network analysis, a statistical method that estimates complex patterns of associations between variables, can be used to model ACEs and CVD. The main goal is to explore the differential impacts of ACE components on CVD outcomes, conditioned on other ACEs and important covariates using network analysis. We also sought to determine which ACEs are most synergistically correlated and subsequently cluster together to affect CVD risk. Methods Our analysis was based on cross-sectional data from the 2020 Behavioral Risk Factor Surveillance System, which included 31,242 adults aged 55 or older (54.6% women, 79.8% whites, mean age of 68.7 ± 7.85 years). CVD outcomes included angina/coronary heart disease (CHD) and stroke prevalence. Mixed graphical models were estimated using the R-package mgm, including all variables simultaneously to elucidate their one-to-one inter-relationships. Next, we conducted Walktrap cluster detection on the estimated networks using the R-package igraph. All analyses were stratified by gender to examine group differences. Results In the network for men, the variable “household incarceration” was most strongly associated with stroke. For women, the strongest connection was between “physical abuse” and stroke, followed by “sexual abuse” and angina/CHD. For men, angina/CHD and stroke were clustered with several CVD risk factors, including depressive disorder, diabetes, obesity, physical activity, and smoking, and further clustered with components of household dysfunction (household substance abuse, household incarceration, and parental separation/divorce). No clusters emerged for women. Conclusions Specific ACEs associated with CVDs across gender may be focal points for targeted interventions. Additionally, findings from the clustering method (especially for men) may provide researchers with valuable information on potential mechanisms linking ACEs with cardiovascular health, in which household dysfunction plays a critical role. Highlights • Network analysis provided insight into potential mechanisms linking ACEs and CVDs.• “Household incarceration” was most strongly associated with stroke for men.• The strongest connection was between “physical abuse” and stroke for women.• For men, CVDs were clustered with CVD risk factors and household dysfunctions.

Project description:Many anticancer therapies cause serious cardiovascular complications that degrade quality of life and cause early mortality in treated patients. Specifically, doxorubicin is known as an effective anticancer agent that causes cardiomyopathy in treated patients. There has been growing interest in defining the role of endothelial cells in cardiac damage by doxorubicin. We have shown in the present study that endothelial nuclei accumulate more intravenously administered doxorubicin than other cardiac cell types. Doxorubicin enhanced cardiac production of the transforming growth factor-β (TGF-β) ligands and nuclear translocation of phospho-Smad3 in both cultured and in vivo cardiac endothelial cells. To examine the role of the TGF-β/mothers against decapentaplegic homolog 3 (Smad3) pathway in cardiac damage by doxorubicin, we used both Smad3 shRNA stable endothelial cell lines and Smad3-knockout mice. We demonstrated using endothelial transcriptome analysis that upregulation of the TGF-β and inflammatory cytokine/cytokine receptor pathways, as well as suppression of cell cycle and angiogenesis by doxorubicin, were alleviated in Smad3-deficient endothelial cells. The results of transcriptomic analysis were validated using qPCR, immunoblotting, and ex vivo aortic ring sprouting assays. Similarly, increased cardiac expression of cytokines and chemokines observed in treated wild-type mice was diminished in treated Smad3-knockout animals. We also detected increased end-diastolic diameter and depressed systolic function in doxorubicin-treated wild-type but not Smad3-knockout mice. This work provides evidence for the critical role of the canonical TGF-β/Smad3 pathway in cardiac damage by doxorubicin.NEW & NOTEWORTHY Microvascular endothelial cells in the heart accumulate more intravenously administered doxorubicin than nonendothelial cardiac cell types. The treatment enhanced the TGF-β/Smad3 pathway and elicited endothelial cell senescence and inflammatory responses followed by adverse cardiac remodeling and dysfunction in wild-type but not Smad3-deficient animals. Our study suggests that the TGF-β/Smad3 pathway contributes to the development of doxorubicin cardiomyopathy and the potential value of novel approaches to ameliorate cardiotoxicity by targeting the Smad3 transcription factor.

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Reversion inducing cysteine rich protein with Kazal motifs and cardiovascular diseases: The RECKlessness of adverse remodeling.

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