Mingyi Wang - Academia.edu (original) (raw)

Papers by Mingyi Wang

Obesity is a top public health concern, and a molecule that safely treats obesity is urgently nee... more Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could ...

Journal of Vascular Research

Age-associated structural and functional remodeling of the arterial wall produces a productive en... more Age-associated structural and functional remodeling of the arterial wall produces a productive environment for the initiation and progression of hypertension and atherosclerosis. Chronic aging stress induces low-grade proinflammatory signaling and causes cellular proinflammation in arterial walls, which triggers the structural phenotypic shifts characterized by endothelial dysfunction, diffuse intimal-medial thickening, and arterial stiffening. Microscopically, aged arteries exhibit an increase in arterial cell senescence, proliferation, invasion, matrix deposition, elastin fragmentation, calcification, and amyloidosis. These characteristic cellular and matrix alterations not only develop with aging but can also be induced in young animals under experimental proinflammatory stimulation. Interestingly, these changes can also be attenuated in old animals by reducing low-grade inflammatory signaling. Thus, mitigating age-associated pro-inflammation and arterial phenotype shifts is a potential approach to retard arterial aging and prevent the epidemic of hypertension and atherosclerosis in the elderly.

Journal of the American Heart Association, Jan 18, 2018

Background Aging exponentially increases the incidence of morbidity and mortality of quintessenti... 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...

Oncotarget, Jan 5, 2018

The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (... 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...

The Medical clinics of North America, 2017

Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hyperten... more Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and an increase of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and an increase in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age. There is an increased prevalence of salt-sensitive hypertension with advancing age that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand.

Handbook of the Biology of Aging, 2016

Gerontology, 2014

ening [1-3]. Studies from animal experiments and human tissue samples demonstrate that age-associ... more ening [1-3]. Studies from animal experiments and human tissue samples demonstrate that age-associated arterial structural and functional changes are the consequence of a proinflammatory phenotypic shift of the arterial cells, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and (myo)fibroblasts (tables 1 , 2) [2-5]. These cellular alterations are closely associated with chronic activation of the angiotensin II (Ang II) signaling cascade [5]. The molecular and cellular events drive arterial wall elastin fragmentation, fibrosis, calcification, glycation, and amyloidosis with advancing age (fig. 1) [2-5]. Proinflammation in the arterial wall is an autoregulated Ang II signaling phenomenon in response to pathophysiological conditions, facilitating 'full-blown' inflammation [5]. This Ang II signaling in the arterial wall with aging originally appears to serve a protective/adaptive biological goal overcoming the changes in hemodynamics and humoral factors, and eventually sets a fertile stage for the initiation and progression of the pathogenesis of hypertension and atherosclerosis in the elderly (fig. 1 ; table 2) [2, 3, 5]. The existing proinflammation lowers the threshold for 'battle signaling triggers' and therefore augments arterial inflammation and increases the incidence of thrombosis, calcification, and lipid pool formation in the advanced arterial lesions with a clinical presentation in the elderly population [1, 6-10]. Thus, suppression of age-associated arterial proinflammation is a rational ap

Cell Metabolism, 2014

Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial d... more Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.

PLoS ONE, 2011

Background: The coincidence of vascular smooth muscle cells (VSMC) infiltration and collagen depo... more Background: The coincidence of vascular smooth muscle cells (VSMC) infiltration and collagen deposition within a diffusely thickened intima is a salient feature of central arterial wall inflammation that accompanies advancing age. However, the molecular mechanisms involved remain undefined. Methodology/Principal Findings: Immunostaining and immunoblotting of rat aortae demonstrate that a triad of proinflammatory molecules, MCP-1, TGF-b1, and MMP-2 increases within the aortic wall with aging. Exposure of VSMC isolated from 8-mo-old rats (young) to MCP-1 effects, via CCR-2 signaling, both an increase in TGF-b1 activity, up to levels of untreated VSMC from 30-mo-old (old) rats, and a concurrent increase in MMP-2 activation. Furthermore, exposure of young VSMC to TGF-b1 increases levels of MCP-1, and MMP-2 activation, to levels of untreated VSMC from old rats. This autocatalytic signaling loop that enhances collagen production and invasiveness of VSMC is effectively suppressed by si-MCP-1, a CCR2 antagonist, or MMP-2 inhibition. Conclusions/Significance: Threshold levels of MCP-1, MMP-2, or TGF-b1 activity trigger a feed-forward signaling mechanism that is implicated in the initiation and progression of adverse age-associated arterial wall remodeling. Intervention that suppressed this signaling loop may potentially retard age-associated adverse arterial remodeling.

Nature, 2006

Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Sacchar... more Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Medical Clinics of North America, 2009

The structure and function of arteries change throughout the lifetime of humans and animals. Epid... more The structure and function of arteries change throughout the lifetime of humans and animals. Epidemiologic studies have found unequivocally that age is the dominant risk factor for hypertension, coronary heart disease, congestive heart failure, and stroke. Specifically, the greatest risk is posed by the most advanced age-associated changes in the arteries, which reflect unsuccessful aging. 1 It is reasonable to hypothesize that specific mechanisms that underlie the arterial substrates that have been altered during aging are intimately linked to the aforementioned cardiovascular diseases. The age-associated arterial changes include lumenal dilation, diffuse intimal and medial thickening, increased stiffness, reduced compliance of central arteries, endothelial dysfunction, impaired nitric oxide (NO) availability, increased reactive oxygen species (ROS), inflammation, and angiogenesis. These age-associated alterations impair arterial regulatory mechanisms and the ability of arteries to adapt, repair, and remodel through the integration of multiple signaling mechanisms. A megacept emerges with the realization that evolution of these age-associated profiles within the arterial wall is strikingly similar to that which develops in arteries of younger animals in response to experimental induction of early atherosclerosis or hypertension. Thus, "aging"associated arterial changes and those associated with the aforementioned "diseases" are fundamentally intertwined at the cellular and molecular levels. In humans, other well-known risk factors (eg, altered lipid metabolism, smoking, and lack of exercise) interact with this arterial substrate that has been altered during aging and that renders the aging artery a fertile soil facilitating the initiation and progression of arterial diseases. The cellular/molecular proinflammatory alterations that underlie arterial aging thus become novel putative candidates to be targeted by interventions aimed at attenuating arterial aging as a major risk factor for cardiovascular diseases. This approach is similar to those aimed at lifestyle and pharmacologic interventions that already have proved effective in preventing or ameliorating arterial diseases associated with aging. This review provides a landscape of central arterial aging and age-disease interactions by attempting to integrate perspectives that range from humans to molecules, with the goal that future therapies for cardiovascular diseases, such as hypertension, also will target the prevention or amelioration of unsuccessful arterial aging.

Journal of Pharmacology and Experimental Therapeutics, 2012

There is no proven therapy or prevention for vascular Ehlers-Danlos syndrome (vEDS), a genetic di... more There is no proven therapy or prevention for vascular Ehlers-Danlos syndrome (vEDS), a genetic disorder associated with the mutation of procollagen type III and characterized by increased fragility of vascular and hollow organ walls. Heterozygous COL3A1-deficient (HT) mice recapitulate a mild presentation of one of the variants of vEDS: haploinsufficiency for collagen III. Adult HT mice are characterized by increased metalloproteinase (MMP) activity, reduced collagen content in the arterial walls, and spontaneous development of various severity lesions in aorta. We hypothesized that chronic treatment with a MMP inhibitor would increase collagen content and prevent the development of spontaneous aortic lesions. HT mice were treated since weaning with the broad-spectrum MMP inhibitor doxycycline added to food. At the age of 9 months MMP-9 expression was twice as high in the tunica media of aorta in untreated HT mice, whereas total collagen content was 30% lower (p Ͻ 0.01) and the cumulative score of aortic lesions was eight times higher than in wild-type (WT) mice (p Ͻ 0.01). After 9 months of doxycycline treatment, MMP-9 activity, collagen content, and lesions in the aortas of HT mice were at the level of those of WT mice (p Ͼ 0.05). In the mouse model of collagen III haploinsufficiency treatment with broad-spectrum MMP inhibitor that was started early in life normalized increased MMP activity, reduced aortic collagen content in adults, and prevented the development of spontaneous aortic lesions. Our findings provide experimental justification for the clinical evaluation of the benefit of doxycycline at least in the haploinsufficient variety of vEDS.

Journal of Molecular and Cellular Cardiology, 2010

Increased activation of the renin-angiotensin-aldosterone system (RAAS) and an increase in oxidat... more Increased activation of the renin-angiotensin-aldosterone system (RAAS) and an increase in oxidative stress are both implicated in age-related cardiac remodeling but their precise interrelationship and linkage to underlying molecular and cellular abnormalities remain to be defined. Recent studies indicate that NADPH oxidases are major sources of oxidative stress and are activated by the RAAS. This study investigated the relationship between the NADPH oxidase system, agerelated cardiac remodeling and its underlying mechanisms. We studied male Fisher 344 cross Brown Norway rats aged 2 months (young rats), 8 months (young adult rats) or 30 months (old rats). Agingdependent increases in blood pressure, cardiomyocyte area, coronary artery remodeling and cardiac fibrosis were associated with increased myocardial NADPH oxidase activity attributable to the Nox2 isoform. These changes were accompanied by evidence of local RAAS activation, increased expression of connective tissue growth factor (CTGF) and TGF-β1, and a significant activation of MMP-2 and MT1-MMP. The changes in old rats were replicated in 8 month old rats that were chronically treated with angiotensin II for 28 days. Increased RAAS activation may drive age-related cardiac remodeling through the activation of Nox2 NADPH oxidase and subsequent increases in MMP activation, fibrosis and cardiomyocyte hypertrophy.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2011

Aging promotes oxidative stress in vascular endothelial and smooth muscle cells, which contribute... more Aging promotes oxidative stress in vascular endothelial and smooth muscle cells, which contribute to the development of cardiovascular diseases. NF-E2-related factor 2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals, leading to adaptive upregulation of numerous reactive oxygen species detoxifying and antioxidant genes. The present study was designed to elucidate age-associated changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature of nonhuman primates. We found that carotid arteries of aged rhesus macaques (Macaca mulatta, age: ≥20 years) exhibit significant oxidative stress (as indicated by the increased 8-iso-PGF2a and 4-HNE content and decreased glutathione and ascorbate levels) as compared with vessels of young macaques (age: ~10 years) that is associated with activation of the redox-sensitive proinflammatory transcription factor, nuclear factor-kappaB. However, age-related oxidative stress does not activate Nrf2 and does not induce Nrf2 target genes (NQO1, GCLC, and HMOX1). In cultured vascular smooth muscle cells (VSMCs) derived from young M mulatta, treatment with H 2 O 2 and high glucose significantly increases transcriptional activity of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured vascular smooth muscle cells cells derived from aged macaques, H 2 O 2-and high glucose-induced Nrf2 activity and Nrf2-driven gene expression are blunted. High glucose-induced H 2 O 2 production was significantly increased in aged vascular smooth muscle cells compared with that in vascular smooth muscle cells from young M mulatta. Taken together, aging is associated with Nrf2 dysfunction in M mulatta arteries, which likely exacerbates age-related cellular oxidative stress, promoting nuclear factor-kappaB activation and vascular inflammation in aging.

Journal of Applied Physiology, 2008

One of the major conceptual advances in our understanding of the pathogenesis of age-associated c... more One of the major conceptual advances in our understanding of the pathogenesis of age-associated cardiovascular diseases has been the insight that age-related oxidative stress may promote vascular inflammation even in the absence of traditional risk factors associated with atherogenesis (e.g., hypertension or metabolic diseases). In the present review we summarize recent experimental data suggesting that mitochondrial production of reactive oxygen species, innate immunity, the local TNF-α-converting enzyme (TACE)-TNF-α, and the renin-angiotensin system may underlie NF-κB induction and endothelial activation in aged arteries. The theme that emerges from this review is that multiple proinflammatory pathways converge on NF-κB in the aged arterial wall, and that the transcriptional activity of NF-κB is regulated by multiple nuclear factors during aging, including nuclear enzymes poly(ADP-ribose) polymerase (PARP-1) and SIRT-1. We also discuss the possibility that nucleophosmin (NPM or nu...

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IEEE Photonics Technology Letters, 2000

Hypertension, 2002

To elucidate potential mechanisms of enhanced type 2 matrix metalloprotease levels and activity w... more To elucidate potential mechanisms of enhanced type 2 matrix metalloprotease levels and activity within the thickened aged rat aorta, the present study measured its mRNA and protein levels and those of its membrane bound activator, MT1-MMP, its endogenous tissue inhibitor, TIMP-2, tissue type, and urokinase plasminogen activators and their receptors, and an inhibitor of plasminogen activation in aortae from Fisher 344X Brown Norway rats, 2 to 30 months of age. Semiquantitative immunohistochemistry, in situ hybridization, and in situ zymography of aortae detected a marked age-associated increase in gelatinolytic activity of type 2 metalloprotease within the thickened intima, internal elastic lamina, and elastic fibers in the inner part of the thickened tunica media, whereas the intimal tissue inhibitor of metalloprotease-2 mRNA and protein levels were not age related. Both activators of plasminogen and their receptors increased approximately 2-fold within the intima between 2 to 30 mo...

Hypertension, 2007

Studies in animal models demonstrate that angiotensin II and its downstream signaling molecules, ... more Studies in animal models demonstrate that angiotensin II and its downstream signaling molecules, that is, matrix metalloproteinases and monocyte chemoattractant protein-1, increase within the diffusely thickened intima of central arteries with aging. Whether such age-related changes occur within the human arterial wall is unknown. We harvested “grossly normal thoracic aortas” from 5 young (20±3 years) and 5 old white males (65±6 years) at necropsy, after death from traumatic causes. The intimae of older samples were markedly and diffusely thickened compared with younger intimae and contained increased levels of angiotensin-converting enzyme, angiotensin II, angiotensin II receptor type 1, matrix metalloproteinases 2/9, monocyte chemoattractant protein-1, and collagen I and III proteins. In situ activities of metalloproteinases 2/9 were also significantly enhanced within old, normal aortas. The thickened intima of older aortas also contained a 5-fold increase in the embryonic form of...

Hypertension, 2003

To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atheroscle... more To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4±0.7 years) and old (20.0±1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody–staining fraction increased by 80% ( P <0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold ( P <0.01); (4) the MT1-MMP antibody–staining fraction increased by 150% ( P <0.001), but the TI...

Current Opinion in Nephrology and Hypertension, 2010

Purpose-Age-associated arterial alterations in cells, matrix, and biomolecules are the foundation... more Purpose-Age-associated arterial alterations in cells, matrix, and biomolecules are the foundation for the initiation and progression of cardiovascular diseases in older persons. This review focuses on the latest advances on the intertwining of aging and disease within the arterial wall at the cell and molecular levels. Recent findings-Endothelial dysfunction, VSMC proliferation/invasion/secretion, matrix fragmentation, collagenization and glycation are characteristics of an age-associated arterial phenotype that creates a microenvironment enriched with reactive oxygen species (ROS) for the pathogenesis of arterial disease. This niche creates an age-associated arterial secretory phenotype (AAASP), which is orchestrated by the concerted effects of numerous age-modified Ang II signaling molecules. Most of these biomolecular, cell, and matrix modifications that comprise the AASP can be elicited by experimental hypertension or atherosclerosis at a younger age. The arterial AAASP also shares features of a senescence associated secretory phenotype (SASP) identified in other mesenchymocytes, i.e. fibroblasts. Summary-A subclinical AAASP evolves during aging. Targeting this subclinical AAASP may reduce the incidence and progression of the quintessential age-associated arterial diseases, i.e. hypertension and atherosclerosis.