Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12

Liu, Shulin; Bajpai, Anamika; Hawthorne, Elizabeth A.; Bae, Yongho; Castagnino, Paola; Monslow, James; Puré, Ellen; Spiller, Kara L.; Assoian, Richard K.

doi:10.1172/jci.insight.122742

Cited by 40 publications

(35 citation statements)

References 69 publications

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“…The expression trend over time is visually shown for each protein. RFU = relative fluorescent unit TA B L E 1 20 examples of common aging plasma proteins with highly intriguing links to aging and/or disease (Glasson et al, 2005) • ADAMTS5 is overexpressed in osteoarthritic cartilage from mice and humans (Lin et al, 2009) • Wwp2 promotes the maintenance of cartilage homeostasis via the suppression of Adamts5 in mice (Mokuda et al, (Kopf et al, 1994) • Genetically disrupting Il6 in mice impairs liver regeneration and causes liver failure (Cressman et al, 1996) (Hunninghake et al, 2009) • Large artery atherosclerosis is associated with a genetic variant in the MMP12 locus and this gene is overexpressed in carotid plaques (Traylor et al, 2014) • In mice deficient in Ldlr, the deletion of Mmp12 protects male mice from both arterial stiffness and atherosclerosis (Liu et al, 2019) NAB1 1.14E−26, −2.01E−03 • NAB1 is upregulated in human heart failure and mice overexpressing Nab1 are protected from induced hypertrophy (Buitrago et al, 2005) • In dogs with moderate heart failure, treatment with rosuvastatin reduces the expression of NAB1 in left ventricular tissue (Zaca et al, 2012…”

Section: A Large Proportion Of Common Aging Plasma Proteins Affect mentioning

confidence: 99%

Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging

et al. 2020

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Section: A Large Proportion Of Common Aging Plasma Proteins Affect mentioning

confidence: 99%

Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging

et al. 2020

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“…In addition, here we found one more unannotated SNP (rs1401366377) elevating the macrophage elastase level, which is known as a physiological marker of accelerated progression of atherosclerosis in transgenic rabbits [112] (Table 4). Looking through our predictions about this gene, we see all three candidate SNP markers accelerating atherogenesis only, whereas the PubMed keyword search utility [38] pointed us to milk products fermented by lactobacilli [113] and estrogen-like nutritional supplements [114], which can decelerate these health problems (Table 4).…”

Section: Human Genes Associated With Autoimmunity-associated Diseasesmentioning

confidence: 99%

Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters Show Stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It

Пономаренко

Рассказов

Chadaeva

et al. 2020

IJMS

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(1) Background: The World Health Organization (WHO) regards atherosclerosis-related myocardial infarction and stroke as the main causes of death in humans. Susceptibility to atherogenesis-associated diseases is caused by single-nucleotide polymorphisms (SNPs). (2) Methods: Using our previously developed public web-service SNP_TATA_Comparator, we estimated statistical significance of the SNP-caused alterations in TATA-binding protein (TBP) binding affinity for 70 bp proximal promoter regions of the human genes clinically associated with diseases syntonic or dystonic with atherogenesis. Additionally, we did the same for several genes related to the maintenance of mitochondrial genome integrity, according to present-day active research aimed at retarding atherogenesis. (3) Results: In dbSNP, we found 1186 SNPs altering such affinity to the same extent as clinical SNP markers do (as estimated). Particularly, clinical SNP marker rs2276109 can prevent autoimmune diseases via reduced TBP affinity for the human MMP12 gene promoter and therefore macrophage elastase deficiency, which is a well-known physiological marker of accelerated atherogenesis that could be retarded nutritionally using dairy fermented by lactobacilli. (4) Conclusions: Our results uncovered SNPs near clinical SNP markers as the basis of neutral drift accelerating atherogenesis and SNPs of genes encoding proteins related to mitochondrial genome integrity and microRNA genes associated with instability of the atherosclerotic plaque as a basis of directional natural selection slowing atherogenesis. Their sum may be stabilizing the natural selection that sets the normal level of atherogenesis.

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“…Atherosclerosis and vascular injury are characterized by neointima formation caused by VSMC accumulation and proliferation within the vessel wall [1,4,5,[9][10][11][12]. In response to vascular injury, VSMCs transition from a highly differentiated state to a de-differentiated state, in which they exhibit increased proliferation, and constitute a substantial part of the neointima [1][2][3].…”

Section: Discussionmentioning

confidence: 99%

“…However, pathologies arise when VSMCs fail to cease proliferation once vascular remodeling has been completed. Uncontrolled VSMC accumulation and proliferation, the main pathologic features of vascular injury, restenosis, and atherosclerosis, contribute to intimal thickening or neointima formation [1,[4][5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Machine learning reveals heterogeneous responses to FAK, Rac, Rho, and Cdc42 inhibition on vascular smooth muscle cell spheroid formation and morphology

Vaidyanathan

Wang

Krajnik

et al. 2020

Preprint

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Hyper proliferation of vascular smooth muscle cells (VSMCs) contributes to neointima formation in atherosclerosis and the response to vascular injury. Understanding how to control VSMC proliferation would advance the effort to treat vascular disease. Drug responses are often different among patients with the same vascular disease condition, making it difficult to cater patientspecific treatments (existence of heterogeneity). Thus, we examined variations in response to drug treatments using VSMC spheroids that mimic vascular disease condition in vivo. FAK and its downstream Rho GTPases (Rac, Rho, and Cdc42) control cell-cell contact and play a key role in vascular pathology. Here, we tested the importance of FAK and Rho GTPases in spheroid formation. VSMC spheroids were made using a hanging-drop method with either inhibitors or vehicle control. Changes in morphology were used as a key indicator of spheroid response to drug treatment. A machine learning (ML) image segmentation (VGG16-U-net) was used to segment the spheroid images. After the morphological features were extracted from the segmented images, a two-level cluster framework was used to cluster VSMC spheroids into different morphologies. We found that FAK and Rho GTPases are required for normal spheroid formation. Next, we analyzed the various morphologies of disrupted spheroids resulting from drug treatment using our ML pipeline. The first-level clustering analysis showed the presence of 4 clusters of spheroids with rounded and disrupted morphologies. The subsequent second-level clustering analysis identified the presence of four distinct morphological clusters among these disrupted spheroids, and they exhibited differential responses to FAK and Rho GTPases inhibition. Particularly, we found FAK and Rho specific morphological phenotypes, thus suggesting that there may be two distinct pathways governing VSMC spheroid formation.Collectively, we revealed there are significant heterogeneities in the drug responses of spheroid formation, which were overlooked in previous analyses. This is our first step towards developing the ML-based method that can be used to assess the effects of different drugs on the VSMC spheroid model for better characterization of pathologic progression of vascular disease.

show abstract

Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12

Cited by 40 publications

References 69 publications

Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging

Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging

Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters Show Stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It

Machine learning reveals heterogeneous responses to FAK, Rac, Rho, and Cdc42 inhibition on vascular smooth muscle cell spheroid formation and morphology

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