Pathophysiology of the atherogenic process

Schwartz, Colin J.; Kelley, Jim; Nerem, Robert M.; Sprague, Eugene A.; Rozek, Marius M.; Valente, Anthony J.; Edwards, Ellen H.; Prasad, Anand; Kerbacher, James J.; Logan, Stephen A.

doi:10.1016/0002-9149(89)90952-1

Cited by 37 publications

(11 citation statements)

References 23 publications

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“…High circulating levels of C3 and C4 have been correlated with increased rates of myocardial infarction in both healthy women and those with established coronary artery disease 9,10 . Traditional models have suggested this systemic source of complement as a participant in the inflammatory responses that occur during development of luminal atherosclerotic lesions 11–14 . This model can be referred to as the “inside‐out” theory of vascular pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Complement Proteins C3 and C4 Bind to Collagen and Elastin in the Vascular Wall: A Potential Role in Vascular Stiffness and Atherosclerosis

Shields

Stolz

Watkins

et al. 2011

Clinical Translational Sci

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Circulating inflammatory mediators including complement activation products participate in the pathogenesis of cardiovascular diseases. As such, previous reports demonstrating the presence of complement proteins within atherosclerotic plaque and on the luminal surface would be anticipated. In contrast, we have recently made the unexpected observation that complement proteins also deposit along the external elastic lamina of mouse aortas in the absence of luminal deposition or plaque development. This suggests that complement activation may play a critical role in the pathogenesis of vascular stiffness and atherosclerosis through a mechanism initiated within the adventitia rather than on the endothelial surface. This hypothesis was tested in the current study by ultrastructural identification of the C3‐ and C4‐binding targets within the adventitia of the mouse aorta. The results demonstrate extensive binding of C3 and C4 to both collagen and elastin fibers within the adventitia in both ApoE(−/−) and C57Bl/6J control mice, as well as the presence of C3 and C4 within perivascular adipose tissue. These observations suggest a potential “outside‐in” mechanism of vascular stiffness during which perivascular adipose may produce C3 and C4 that bind to collagen and elastin fibers within the adventitia through covalent thiolester bonds, leading to increased vascular stiffness. Clin Trans Sci 2011; Volume 4: 146–152

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Section: Discussionmentioning

confidence: 99%

Complement Proteins C3 and C4 Bind to Collagen and Elastin in the Vascular Wall: A Potential Role in Vascular Stiffness and Atherosclerosis

Shields

Stolz

Watkins

et al. 2011

Clinical Translational Sci

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“…19 Specific roles of the low-density lipoprotein (LDL) receptor and macrophage scavenger receptor were subsequently identified. [20][21][22][23] In the early 1990s, studies evaluated inflammatory cell functions such as chemotaxis, transmigration of monocytes, cytokine secretion, and inflammatory cell retention and egress [24][25][26] in atherosclerosis. The important roles of cytokines and growth factors such as tumor necrosis factor-a, 27 interleukin-12, 28 interferon-g, 29 platelet-derived growth factor, endothelial expression of vascular adhesion molecules, [30][31][32] and chemokines 33 that could participate in inflammatory cell recruitment were identified.…”

Section: Inflammation In Atherosclerosis: a Brief Historic Perspectivementioning

confidence: 99%

Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease

Swaminathan

Shah

2011

Kidney International

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A substantial body of evidence has accumulated linking an increased incidence of cardiovascular disease in patients with acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD). A multitude of novel risk factors related to decreased kidney function might interact with the renal and systemic immune systems involved in renal injury and repair to participate in accelerated atherogenesis (Immune inflammation-Renal injury-Atherosclerosis--the IRA Paradigm). In this review, we will discuss several of these novel risk factors and present the potential for the role of the immune-inflammatory system in accelerated atherosclerosis of kidney disease.

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“…Elevated permeability of vascular endothelium to LDL is characteristic of focal sites within the vasculature that are prone to the development of atherosclerosis [3]. In animal studies, lesion prone areas have been detected consistently before plaques become visible by their uptake of the protein-binding dye Evans Blue [4]. These lesion prone (blue) areas have also been shown to exhibit an enhanced permeability to albumin, LDL and cholesterol [5-7].…”

Section: Introductionmentioning

confidence: 99%

The role of apoptosis in LDL transport through cultured endothelial cell monolayers

Cancel

Tarbell

2010

Atherosclerosis

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We have previously shown that leaky junctions associated with dying or dividing cells are the dominant pathway for LDL transport under convective conditions, accounting for more than 90% of the transport [1]. To explore the role of apoptosis in the leaky junction pathway, TNFα and cycloheximide (TNFα/CHX) were used to induce an elevated rate of apoptosis in cultured bovine aortic endothelial cell (BAEC) monolayers and the convective fluxes of LDL and water were measured. Treatment with TNFα/CHX induced a 18.3-fold increase in apoptosis and a 4.4-fold increase in LDL permeability. Increases in apoptosis and permeability were attenuated by treatment with the caspase inhibitor Z-VAD-FMK. Water flux increased by 2.7-fold after treatment with TNFα/CHX, and this increase was not attenuated by treatment with Z-VAD-FMK. Immunostaining of the tight junction protein ZO-1 showed that TNFα/CHX treatment disrupts the tight junction in addition to inducing apoptosis. This disruption is present even when Z-VAD-FMK is used to inhibit apoptosis, and likely accounts for the increase in water flux. We found a strong correlation between the rate of apoptosis and the permeability of BAEC monolayers to LDL. These results demonstrate the potential of manipulating endothelial monolayer permeability by altering the rate of apoptosis pharmacollogicaly. This has implications for the treatment of atherosclerosis.

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Pathophysiology of the atherogenic process

Cited by 37 publications

References 23 publications

Complement Proteins C3 and C4 Bind to Collagen and Elastin in the Vascular Wall: A Potential Role in Vascular Stiffness and Atherosclerosis

Complement Proteins C3 and C4 Bind to Collagen and Elastin in the Vascular Wall: A Potential Role in Vascular Stiffness and Atherosclerosis

Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease

The role of apoptosis in LDL transport through cultured endothelial cell monolayers

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