Insights into bone morphogenetic proteins in cardiovascular diseases

Ye, Di; Liu, Yinghui; Pan, Heng; Feng, Yanqin; Lu, Xiyi; Liren, Gan; Wan, Jun; Ye, Jing

doi:10.3389/fphar.2023.1125642

Cited by 14 publications

(11 citation statements)

References 256 publications

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“…This agrees with the experimentally observed function of BMP9, which is to preserve EC quiescence [117,95,119]. However, BMPR2 loss in PAECs reverses the effect of BMP9 [118,120].…”

Section: 31supporting

confidence: 91%

“…Additionally, we performed a semantic radiate analysis with BMP2 as the source resulting in a significant association with bone mineralization and positive regulation of osteoblast proliferation (Table 1 row 18). Not all the effects of BMP2 signaling are beneficial for PH patients, as BMP2 signaling can induce vascular calcification greatly diminishing the therapeutic potential of BMP2 in the treatment of PH [116, 117, 118].…”

Section: Resultsmentioning

confidence: 99%

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ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

Weinstein,

Carlsen,

Schulz

et al. 2023

Preprint

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Pulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation. Using our graph-powered knowledge mining softwareLifelikein combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs. In PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities ofLifelike, led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to Activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH.Lifelikeelucidated the interplay between G-protein, interleukin 6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis. The results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs usingLifelike’s diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe thatLifelikeand our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.

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“…This agrees with the experimentally observed function of BMP9, which is to preserve EC quiescence [117,95,119]. However, BMPR2 loss in PAECs reverses the effect of BMP9 [118,120].…”

Section: 31supporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

Weinstein,

Carlsen,

Schulz

et al. 2023

Preprint

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“…CRIM1 modulates activity of bone morphogenic proteins, members of the TGFβ superfamily that are known to play roles in cardiac development and disease pathophysiology in HF, pulmonary arterial hypertension, and atherosclerosis. 39 Both THBS2 and TIMP1 are critical regulators of tissue homeostasis with roles in ECM remodeling, angiogenesis, and cell growth/differentiation, and have been extensively implicated in HF pathogenesis, 40,41 including in recent plasma proteome studies. [42][43][44] Other proteome features of particularly high interest have been linked to migration of various immune cell subsets in tissue homeostasis-specifically DLL1 (a ligand of Notch receptors), ESAM (endothelial cell adhesion molecule), JAM2 (involved in cell migration), and LAYN (involved in focal adhesion).…”

Section: Cell Migration and Tissue Homeostasismentioning

confidence: 99%

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure

Peterson,

Hahn,

Moaddel

et al. 2024

Preprint

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Background: People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH. Methods: We performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Associations with HIV serostatus and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression. Results: Among 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m2. Of 2594 analyzed proteins, 439 were associated with HIV serostatus, independent of demographics, hepatitis C virus infection, renal function, and substance use (FDR<0.05). We identified 73 of these proteins as candidate contributors to the independent association between positive HIV serostatus and higher LAVi, enriched in tumor necrosis factor (TNF) signaling and immune checkpoint proteins regulating T cell, B cell, and NK cell activation. We identified one protein cluster associated with LAVi and HIV regardless of HIV viral suppression status, which comprised 42 proteins enriched in TNF signaling, ephrin signaling, and extracellular matrix (ECM) organization. This protein cluster and 30 of 73 individual proteins were associated with incident HF among 2273 older PWOH (age 68±9 years; 52% female; 8.5±1.4 years of follow-up). Conclusion: Proteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.

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“…Kielin/chordin‐like protein (KCP) is a secretory protein with 18 cysteine‐rich domains 4 . Previous studies have shown that KCP is an enhancer of bone morphogenetic proteins (BMP) signaling and suppressor of transforming growth factor β (TGF‐β) signaling, 4 which are both involved in the regulation of fibrosis and cardiac remodeling 5 . It has been reported that KCP promotes BMP7 binding to its receptor, increasing the phosphorylation of intracellular Smad1, thereby ameliorating renal fibrosis 6 .…”

Section: Introductionmentioning

confidence: 99%

“…4 Previous studies have shown that KCP is an enhancer of bone morphogenetic proteins (BMP) signaling and suppressor of transforming growth factor β (TGF-β) signaling, 4 which are both involved in the regulation of fibrosis and cardiac remodeling. 5 It has been reported that KCP promotes BMP7 binding to its receptor, increasing the phosphorylation of intracellular Smad1, thereby ameliorating renal fibrosis. 6 Meanwhile, KCP can inhibit activin A and TGF-β1mediated signal transduction in a paracrine manner through Smad2/3 pathway in renal epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Kielin/chordin‐like protein deficiency aggravates pressure overload‐induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice

Xu,

Zheng,

Pan

et al. 2024

The FASEB Journal

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Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin‐like protein (KCP) is a secretory protein with 18 cysteine‐rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real‐time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload‐induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide‐type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down‐regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload‐induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up‐regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

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Insights into bone morphogenetic proteins in cardiovascular diseases

Cited by 14 publications

References 256 publications

ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure

Kielin/chordin‐like protein deficiency aggravates pressure overload‐induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice

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