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Research Interests: Endocrinology, Chemistry, Aging, Enzyme Inhibitors, Medicine, and 15 moreInternal Medicine, Hypertension, Collagen, Blood Pressure, Animals, Male, Clinical Sciences, Elastin, Rats, Matrix Metalloproteinases, Hydroxamic Acids, Arteritis, Monocyte, Cardiovascular medicine and haematology, and Matrix metalloproteinase inhibitors
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Adult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload (∼30% increases in heart rate, ejection fraction and cardiac output) for up to a... more
Adult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload (∼30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here we show that despite markedly increased cardiac work, classical cardiac hypertrophy markers were absent in TGAC8, total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes and a network of small interstitial non-cardiac myocytes, manifesting increased proliferation markers and compared to WT. Protein synthesis, proteosome activity, autophagy, and Nrf-2, Hsp90α, ACC2 protein levels were increased in TGAC8, but LV ATP and phosphocreatine levels in vivo did not differ by genotype. 2,323 transcripts and 2,184 proteins identified in unbiased omics analyses, spanning a wide arr...
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Background: Milk fat globule epidermal growth factor VIII (MFG-E8), a secreted membrane glycoprotein, is an inflammatory signaling molecule, promoting the proliferation and invasion of vascular smooth muscle cells in vitro. MFG-E8 also is... more
Background: Milk fat globule epidermal growth factor VIII (MFG-E8), a secreted membrane glycoprotein, is an inflammatory signaling molecule, promoting the proliferation and invasion of vascular smooth muscle cells in vitro. MFG-E8 also is a bridging molecule that connects vascular smooth muscle cells to elastic fibers, forming elastin-smooth muscle unit, an essential contractile element within arterial medial wall. The inflammatory effects of MFG-E8 signaling between cells and matrix on adverse arterial remodeling with advancing age, however, remains unknown. Methods and Results: In this study, homozygous MFG-E8 knockout (MFG-E8 KO, n=50) and age-matched wild type male mice (WT, n=50) were investigated. Western blot analysis confirmed that MFG-E8 protein was enriched in the aortic walls of WT mice, but not detected in MFG-E8 KO animals (Fig. A) . In WT, aortic MFG-E8 protein was markedly increased (~18-fold, p<0.0001) in 96-week-old versus 40-week-old ( Fig. B ). Importantly, aor...
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BackgroundAngiotensin II (Ang II) and milk fat globule-epidermal growth factor VIII (MFG-E8) are involved in age-associated arterial remodeling; however, the inflammatory role of MFG-E8 in Ang II associated arterial remodeling with aging... more
BackgroundAngiotensin II (Ang II) and milk fat globule-epidermal growth factor VIII (MFG-E8) are involved in age-associated arterial remodeling; however, the inflammatory role of MFG-E8 in Ang II associated arterial remodeling with aging remains unknown.Methods and ResultsIn this study, 30-week-old MFG-E8 knock out (KO) and age-matched wild-type (WT) mice were infused with Ang II or saline. After infusion the with Ang II, the aortic molecular, cellular, and structural remodeling were observed in mice and compared to those infused with saline, but these effects were dependent on the expression of MFG-E8: (1) In the WT mice, Ang II infusion substantially increased intimal-medial thickness, elastic lamina degradation, collagen deposition, and the proliferation of VSMCs; in contrast, in the KO mice, these effects were significantly reduced; (2) In the WT mice, Ang II treatment significantly increased the activation and expression of MMP2, TGF-β1, and its downstream signaling molecule p-...
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Current models stipulate that B cells and antibodies function during atherosclerosis in two distinct ways based on antibody isotype, where IgM is protective and IgG is inflammatory. To examine this model, we generated ApoE-/- Aid-/- mice,... more
Current models stipulate that B cells and antibodies function during atherosclerosis in two distinct ways based on antibody isotype, where IgM is protective and IgG is inflammatory. To examine this model, we generated ApoE-/- Aid-/- mice, which are unable to produce IgG antibodies due to the absence of activation-induced deaminase (AID) but maintain high plasma cholesterol due to the absence of apolipoprotein E (APOE). We saw a dramatic decrease in plaque formation in ApoE-/- Aid-/- mice compared to ApoE-/- mice. Rigorous analysis of serum antibodies revealed both ApoE-/- and ApoE-/- Aid-/- mice had substantially elevated titers of IgM antibodies compared to C57BL/6J controls, suggesting a more complex dynamic than previously described. Analysis of antigen specificity demonstrated that ApoE-/- Aid-/- mice had elevated titers of antibodies specific to malondialdehyde-oxidized low density lipoprotein (MDA-oxLDL), which has been shown to block macrophage recruitment into plaques. Conve...
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Milk fat globule-EGF factor 8 (MFG-E8) protein increases with age and is mainly secreted by vascular smooth muscle cells in the arterial wall. Here, we investigated the role of MFG-E8 signaling during proinflammation, elastolysis,... more
Milk fat globule-EGF factor 8 (MFG-E8) protein increases with age and is mainly secreted by vascular smooth muscle cells in the arterial wall. Here, we investigated the role of MFG-E8 signaling during proinflammation, elastolysis, fibrosis, and calcification within the aging arterial wall. In vivo studies indicated that (1) Elastic lamina breaks collagen deposition and calcium-phosphorus products were markedly increased in the aging arterial wall of rats; (2) MFG-E8 protein abundance was markedly increased while intact tropoelastin (TPELN), an element of repair of the elastic fibers, was markedly decreased in the aging arterial wall of rats; (3) The absence of MFG-E8 markedly alleviated age-associated increases in elastic lamina breaks, collagen deposition and calcium-phosphorus products in mice; and (4) MFG-E8 deficiency significantly decreased age-associated increases in matrix metalloproteinase type II (MMP-2) activation, alkaline phosphatase, and runt-related transcription facto...
Background Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial... more
Background Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction ( CR ) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated. Methods and Results Aortae were harvested from young (6-month-old) and old (24-month-old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age-associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented...
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The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (TGF-β1) and functionally attenuates its fibrogenic signaling in the vascular smooth muscle cells (VSMCs) of the arterial wall. Angiotensin II... more
The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (TGF-β1) and functionally attenuates its fibrogenic signaling in the vascular smooth muscle cells (VSMCs) of the arterial wall. Angiotensin II (Ang II) amplifies TGF-β1 activation in the VSMCs of the arterial wall with aging. In this study, we hypothesized that a reduced expression of the protein vasorin plays a contributory role in magnifying Ang II-associated fibrogenic signaling in the VSMCs of the arterial wall with aging. The current study shows that vasorin mRNA and protein expression were significantly decreased both in aortic wall and VSMCs from old (30 mo) vs. young (8 mo) FXBN rats. Exposing young VSMCs to Ang II reduced vasorin protein expression to the levels of old untreated cells while treating old VSMCs with the Ang II type AT1 receptor antagonist Losartan upregulated vasorin protein expression up to the levels of young. The physical interaction between vasorin and TGF-β1 w...
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Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory... more
Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young ...
Research Interests: Endocrinology, Aging, Biology, Medicine, Multidisciplinary, and 14 moreSignal Transduction, Internal Medicine, Animals, Male, PLoS one, Calpain, Rats, Calpastatin, Angiotensin II, Aorta, Protein Biosynthesis, Matrix Metalloproteinase, Vascular Smooth Muscle, and reverse transcriptase polymerase chain reaction
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Research Interests: Depression, Biotechnology, Gene Silencing, Macular Degeneration, Lipids, and 15 moreCell line, Humans, Cholesterol, Animals, Cell, Lipid metabolism, Apolipoprotein B, apoB, Age related macular degeneration, Clinical Sciences, Lipoproteins, Free Fatty Acid, Lipoprotein a, Fatty Acid Binding Protein, and Intracellular Transport
Research Interests: Endocrinology, Aging, Biology, Oxidative Stress, Medicine, and 15 moreGene expression, Endothelial Cells, Reactive Oxygen Species, Vasculitis, Animals, Male, Glutathione, Transcription Factor, Clinical Sciences, Hydrogen Peroxide, Macaca Mulatta, Oxidants, Vascular Smooth Muscle, Carotid Arteries, and Tissue culture techniques
Age-associated central arterial wall stiffness is linked to extracellular matrix remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase 2 (MMP2) and calpain-1 expression and... more
Age-associated central arterial wall stiffness is linked to extracellular matrix remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase 2 (MMP2) and calpain-1 expression and activity in the arterial wall. However, the role of calpain-1 in MMP2 activation and extracellular matrix remodeling remains unknown. Dual histo-immunolabeling demonstrates colocalization of calpain-1 and MMP2 within old rat vascular smooth muscle cells. Overexpression of calpain-1 induces MMP2 transcripts, protein levels, and activity, in part, by increasing the ratio of membrane type 1 MMPs to tissue inhibitor of metalloproteinases 2. These effects of calpain-1 overexpression-induced MMP2 activation are linked to increased collagen I and III production and vascular calcification. In addition, overexpression of calpain-1 also induces transforming growth factor-β1/Smad signaling, elastin degradation, alkaline phosphatase activation, and total calcium conte...
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Age-associated arterial remodeling involves arterial wall collagen deposition and elastin fragmentation, as well as an increase in arterial pressure. This arterial remodeling is linked to proinflammatory signaling, including transforming... more
Age-associated arterial remodeling involves arterial wall collagen deposition and elastin fragmentation, as well as an increase in arterial pressure. This arterial remodeling is linked to proinflammatory signaling, including transforming growth factor-β1, monocyte chemoattractant protein 1, and proendothelin 1, activated by extracellular matrix metalloproteinases (MMPs) and orchestrated, in part, by the transcriptional factor ets-1. We tested the hypothesis that inhibition of MMP activation can decelerate the age-associated arterial proinflammation and its attendant increase in arterial pressure. Indeed, chronic administration of a broad-spectrum MMP inhibitor, PD166739, via a daily gavage, to 16-month–old rats for 8 months markedly blunted the expected age-associated increases in arterial pressure. This was accompanied by the following: (1) inhibition of the age-associated increases in aortic gelatinase and interstitial collagenase activity in situ; (2) preservation of the elastic ...
Research Interests: Endocrinology, Chemistry, Aging, Enzyme Inhibitors, Medicine, and 15 moreInternal Medicine, Hypertension, Collagen, Blood Pressure, Animals, Male, Clinical Sciences, Elastin, Rats, Matrix Metalloproteinases, Hydroxamic Acids, Arteritis, Monocyte, Cardiovascular medicine and haematology, and Matrix metalloproteinase inhibitors
Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have... more
Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30 months) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.3-fold in abundance in old aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II and monocyte chemoattractant protein (MCP)-1 within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VSMCs from young aorta to angiotensin ...
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SummaryAn accumulation of milk fat globule EGF‐8 protein (MFG‐E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or atherosclerosis. MFG‐E8 induces VSMC invasion, but... more
SummaryAn accumulation of milk fat globule EGF‐8 protein (MFG‐E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or atherosclerosis. MFG‐E8 induces VSMC invasion, but whether it affects VSMC proliferation, a salient feature of arterial inflammation, is unknown. Here, we show that in the rat arterial wall in vivo, PCNA and Ki67, markers of cell cycle activation, increase with age between 8 and 30 months. In fresh and early passage VSMC isolated from old aortae, an increase in CDK4 and PCNA, an increase in the acceleration of cell cycle S and G2 phases, decrease in the G1/G0 phase, and an increase in PDGF and its receptors confer elevated proliferative capacity, compared to young VSMC. Increased coexpression and physical interaction of MFG‐E8 and integrin αvβ5 occur with aging in both the rat aortic wall in vivo and in VSMC in vitro. In young VSMC in vitro, MFG‐E8 added exogenously, or overexpressed endogenously, trigg...
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Research Interests: Obesity, Asthma, Medicine, Energy Metabolism, Dietary Restriction, and 15 moreHumans, Internal Medicine, Calorie restriction, Lipid metabolism, Lung, General Health, Adult, Fatty Acid, Biological markers, Caloric Restriction, Calorie, Biochemistry and cell biology, Free Radical Biology, Inflammation Mediators, and dietary intervention
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Mitochondrial metabolism is highly responsive to nutrient availability and ongoing activity in neuronal circuits. The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown.... more
Mitochondrial metabolism is highly responsive to nutrient availability and ongoing activity in neuronal circuits. The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown. Mild mitochondrial uncoupling enhances cellular energy expenditure in mitochondria and can be induced with 2, 4-dinitrophenol (DNP), a proton ionophore previously used for weight loss. We found that DNP treatment reduces mitochondrial membrane potential, increases intracellular Ca(2+) levels and reduces oxidative stress in cerebral cortical neurons. Gene expression profiling of the cerebral cortex of DNP-treated mice revealed reprogramming of signaling cascades that included suppression of the mTOR and insulin - PI3K - MAPK pathways, and up-regulation of tuberous sclerosis complex 2, a negative regulator of mTOR. Genes encoding proteins involved in autophagy processes were up-regulated in response to DNP. CREB (cAMP-response element-binding protein) si...
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Research Interests: Endocrinology, Neuroscience, Cognitive Science, Cognition, Long Term Potentiation, and 15 moreBiology, Diet, Medicine, Insulin Resistance, Hippocampus, Internal Medicine, Animals, Neuronal Plasticity, Fluorescent Antibody Technique, Rats, Dietary Carbohydrates, Neurotrophic Factors, Neurosciences, Hippocampal formation, and Dietary fats
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Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory... more
Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young ...