Evidence for an exclusive association of matrix metalloproteinase-9 with dysfunctional high-density lipoprotein: A novel finding

Sini, S.; Deepa, D.; Harikrishnan, S; Jayakumari, N.

doi:10.1016/j.atherosclerosis.2014.06.007

Cited by 10 publications

(10 citation statements)

References 36 publications

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“…HDL isolated from each healthy subject and CAD patient was first evaluated for its antioxidant property by assessing its ability to inhibit LDL oxidation in vitro, using fluorescence assay. The air-saline oxidation of LDL (control LDL, pooled from five healthy subjects) gave rise to a corresponding fluorescence intensity ( However, in consistent with our previous reports, [7,8] we observed dysfunctionality and proinflammatory property in HDL derived from all CAD patients (piHDL), as it failed to protect LDL from oxidation. In fact, co-incubation of LDL with piHDL enhanced LDL oxidation (∼twofold increase in fluorescence intensity).…”

Section: Hdl From Cad Patient Is Dysfunctional and Proinflammatorysupporting

confidence: 90%

“…[4,7,8,34,37] More studies are needed to determine the exact pathways and apoptotic regulatory molecules participating in this process. [4,7,8,34,37] More studies are needed to determine the exact pathways and apoptotic regulatory molecules participating in this process.…”

Section: Discussionmentioning

confidence: 99%

“…It can undergo pronounced compositional and functional modification in subjects under certain conditions associated with acute-phase response and inflammation. [7,8] HDL may be viewed as a shuttle that can be either antiinflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids. [5] We have recently reported that HDL from patients with established CAD, exhibits dysfunctionality with total reduction in its antioxidant property to inhibit LDL oxidation in vitro and it also stimulates pro-oxidant effects in human monocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Further characterization demonstrated an exclusive association of a protease, matrix metalloproteinase-9 with dysfunctional HDL. [7,8] HDL may be viewed as a shuttle that can be either antiinflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids. [9] HDL normally plays a cardioprotective role by promoting RCT which is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma compartment.…”

Section: Introductionmentioning

confidence: 99%

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Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease

Sini

Deepa

Harikrishnan

et al. 2018

J Biochem & Molecular Tox

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High density lipoprotein (HDL)-macrophage interactions have the potential to modulate macrophage function in a beneficial way to prevent the development of lipid-loaded foam cell formation in atherosclerosis. Although HDL is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. Here, we examined the effect of dysfunctional-HDL from patients with coronary artery disease, on macrophage function in comparison to functional-HDL from controls. Exposure of macrophages to dysfunctional-HDL for 24 h resulted significant increase in cellular oxidative stress, cholesterol, and cytotoxicity. It also stimulated mitochondrial membrane depolarization, DNA damage, apoptosis, and cleavage of poly (ADP-ribose) polymerase, which are characteristics of proapoptotic pathways. In contrast, functional-HDL treatment maintained cholesterol homeostasis, essential membrane potential, DNA integrity, and cell survival. These results demonstrate that HDL from coronary artery disease (CAD) patient promotes proatherogenic effects that in turn trigger macrophage apoptosis, an important feature in atherogenesis and thereby providing new insight in our understanding of the atherogenic mechanisms.

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Section: Hdl From Cad Patient Is Dysfunctional and Proinflammatorysupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease

Sini

Deepa

Harikrishnan

et al. 2018

J Biochem & Molecular Tox

Self Cite

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“…MMP-9 expression was enhanced in untreated diabetic apoE-/-mice and absent in insulin-treated mice [187]. Moreover, MMP-9 was associated with dysfunctional HDL, which are lipoproteins with antiatherogenic functions [188]. MMP-12 is involved in plaque progression and instability, while MMP-14 expression is enhanced in a distinct subpopulation of foam cell macrophages which have TIMP-3 downregulated [189].…”

Section: Vascular Remodeling Related Enzymes Matrix Metalloproteasesmentioning

confidence: 90%

Enzymatic Targets in Atherosclerosis

Fuior¹,

Trusca²,

Roman³

et al. 2015

J Mol Genet Med

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Atherosclerosis, a prime cause of mortality across the developed societies, was targeted by diverse therapeutic strategies. These evolved in response to the complex etiology and evolution of the disease. Many enzymes are associated with atherosclerosis, either in the main stream of lipid biosynthesis and transport or in the collateral and intertwined pathways of oxidative stress, inflammation, vascular remodeling or chromatin stability and are therefore revised herein. Enzyme exploration led to important developments. At the beginning, there were the statins, derived as inhibitors of hydroxy-methyl-glutaryl CoA (HMG-CoA) reductase, currently used widely to decrease lipid levels. At the other end, the inhibitors of the recently discovered proprotein convertase subtilisin/kexin type 9 (PCSK9) are awaiting the validation in clinical trials with great hopes for the future. In between, one can find some palliatives, as aspirin, an inhibitor of cyclooxygenase (COX), but also many invalidated candidates. Classical pharmacological data and newer approaches, like genetic knockouts in murine atherosclerosis models, are reviewed in order to appreciate the involvement of a particular enzyme in atherogenesis. However, the pursuit of an efficacious drug has been long and, in many cases, disappointing. Conclusions can be drawn from the overview of both successes and failures, in a quest for the best.

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High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling

et al. 2016

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Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content. Using western blotting, we identified that piHDL profoundly upregulated the expression of scavenger receptor CD36 and suppressed the expression of ABCG1 and SRB1 in macrophages, thereby facilitating cholesterol influx capacity of macrophages. We then identified that CD36 did not act alone, indeed it was activated in macrophages along with ERK/MAPK, in response to piHDL, which in turn led to lipid accumulation as well as proinflammatory response via activation of NFkB and subsequent release of proinflammatory markers-TNF-ά and MMP-9. These effects were confirmed using pharmacological inhibitors for either CD36 or ERK/MAPK. Furthermore, piHDL treatment moderately activated PPAR-γ and Nrf2, the known regulators of CD36 in macrophages, suggesting that the two forms of HDL differentially regulate CD36 expression. Taken together, the results demonstrate that a novel CD36-ERK/MAPK-dependent mechanism is involved in macrophage lipid accumulation by piHDL, there by revealing the importance of functional deficiency in HDL and its potential link to atherogenesis.

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Evidence for an exclusive association of matrix metalloproteinase-9 with dysfunctional high-density lipoprotein: A novel finding

Cited by 10 publications

References 36 publications

Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease

Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease

Enzymatic Targets in Atherosclerosis

High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling

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