Aortic Valve Apoptosis, Cell Proliferation and Atherosclerosis in Experimental Hypercholesterolemia

Matrix metalloproteinases (MMPs) and cathepsins are proteolytic enzymes that are upregulated in diseased aortic valve cusps. The objective of this study was to investigate whether elevated cyclic stretch causes an increased expression and activity of these proteolytic enzymes in the valve cusp. Circumferentially oriented fresh porcine aortic valve cusp sections were stretched to 10% (physiological), 15% (pathological), and 20% (hyperpathological) in a tensile stretch bioreactor for 24 and 48 h. The expression and activity of MMP-1, MMP-2, MMP-9, tissue inhibitor of MMP-1, and cathepsin L, S, and K were quantified and compared with fresh controls. Cell proliferation and apoptosis were also analyzed. As a result, at 10% physiological stretch, the expression and activity of remodeling enzymes were comparable with fresh controls. At 15% stretch, the expression of MMP-1, -2, -9 and cathepsin S and K were upregulated, whereas the expression of cathepsin L was downregulated compared with controls. A similar trend was observed at 20% stretch, but the magnitudes of upregulation and downregulation of the expression were less than those observed at 15%. In addition, there were significantly higher cell proliferation and apoptosis at 20% stretch compared with those of other treatment groups. In conclusion, elevated mechanical stretch on aortic valve cusps may detrimentally alter the proteolytic enzyme expression and activity in valve cells. This may trigger a cascade of events leading to an accelerated valve degeneration and disease progression.

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Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00209.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. H1143-H1154 ◽

Cited By ~ 8

Author(s):

Dorothy Amofa ◽

Alexia Hulin ◽

Yuji Nakada ◽

Hesham A. Sadek ◽

Katherine E. Yutzey

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Aortic Valve ◽

Chicken Embryo ◽

Heart Valves ◽

Fibrillar Collagen ◽

Organ Cultures ◽

Aortic Valves ◽

Valve Development ◽

Developing Heart

During postnatal heart valve development, glycosaminoglycan (GAG)-rich valve primordia transform into stratified valve leaflets composed of GAGs, fibrillar collagen, and elastin layers accompanied by decreased cell proliferation as well as thinning and elongation. The neonatal period is characterized by the transition from a uterine environment to atmospheric O2, but the role of changing O2 levels in valve extracellular matrix (ECM) composition or morphogenesis is not well characterized. Here, we show that tissue hypoxia decreases in mouse aortic valves in the days after birth, concomitant with ECM remodeling and cell cycle arrest of valve interstitial cells. The effects of hypoxia on late embryonic valve ECM composition, Sox9 expression, and cell proliferation were examined in chicken embryo aortic valve organ cultures. Maintenance of late embryonic chicken aortic valve organ cultures in a hypoxic environment promotes GAG expression, Sox9 nuclear localization, and indicators of hyaluronan remodeling but does not affect fibrillar collagen content or cell proliferation. Chronic hypoxia also promotes GAG accumulation in murine adult heart valves in vivo. Together, these results support a role for hypoxia in maintaining a primitive GAG-rich matrix in developing heart valves before birth and also in the induction of hyaluronan remodeling in adults. NEW & NOTEWORTHY Tissue hypoxia decreases in mouse aortic valves after birth, and exposure to hypoxia promotes glycosaminoglycan accumulation in cultured chicken embryo valves and adult murine heart valves. Thus, hypoxia maintains a primitive extracellular matrix during heart valve development and promotes extracellular matrix remodeling in adult mice, as occurs in myxomatous disease.

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Tgfβ1-Cthrc1 Signaling Axis Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316450 ◽

2021 ◽

Author(s):

Emily M. Nordquist ◽

Punashi Dutta ◽

Karthik M. Kodigepalli ◽

Carol Mattern ◽

Michael R. McDermott ◽

...

Keyword(s):

Cell Proliferation ◽

Aortic Valve ◽

Heart Valve ◽

Barrier Function ◽

Endothelial Injury ◽

Endothelial Barrier ◽

Wild Type ◽

Endothelial Barrier Function ◽

Short Term ◽

Signaling Axis

Objective: Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response to injury at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16–18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 ( Tgfβ1 ) and the glycoprotein, collagen triple helix repeat containing 1 ( Cthrc1 ). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. Conclusions: Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.

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Interleukin 1 beta induces matrix metalloproteinase expression in human aortic valve myofibroblasts in vitro and promotes cell proliferation

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(03)82721-3 ◽

2003 ◽

Vol 41 (6) ◽

pp. 500

Author(s):

Jens J. Kaden ◽

Refika Kilic ◽

Aslihan Sarikoc ◽

Karl K. Haase ◽

Carl-Erik Dempfle ◽

...

Keyword(s):

Cell Proliferation ◽

Aortic Valve ◽

Matrix Metalloproteinase ◽

Interleukin 1 ◽

Interleukin 1 Beta ◽

Human Aortic Valve

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An Assessment of Ca-Naphthenate-Epon Mixtures as Standards for Calcium Quantification in Aortic Valve Leaflets

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100054558 ◽

1982 ◽

Vol 40 ◽

pp. 390-391

Author(s):

Kathryn N. Colonna ◽

Sydney S. Breese ◽

Susan C. Sellers ◽

J. David Deck

Keyword(s):

Aortic Valve ◽

Aortic Valves ◽

X Ray ◽

Aortic Valve Leaflets

Qualitative x-ray microanalytical studies used to demonstrate calcium in bioprosthetic aortic valves have shown that it occurs in a range of morphological forms. A consistent and reproducible standard for measuring calcium was necessary to investigate whether these forms represented varying concentrations of calcium. To provide such a standard, we tested a series of calcium naphthenate-epon mixtures.

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Fibroblasts During Hypertrophic Scar Formation and Resolution

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100072587 ◽

1973 ◽

Vol 31 ◽

pp. 428-429

Author(s):

C. W. Kischer

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Cell Proliferation ◽

Fine Structure ◽

Metabolic Activity ◽

Hypertrophic Scar ◽

Normal Skin ◽

Ground Substance ◽

Hypertrophic Scars ◽

Scanning Electron

The morphology of the fibroblasts changes markedly as the healing period from burn wounds progresses, through development of the hypertrophic scar, to resolution of the scar by a self-limiting process of maturation or therapeutic resolution. In addition, hypertrophic scars contain an increased cell proliferation largely made up of fibroblasts. This tremendous population of fibroblasts seems congruous with the abundance of collagen and ground substance. The fine structure of these cells should reflect some aspects of the metabolic activity necessary for production of the scar, and might presage the stage of maturation.A comparison of the fine structure of the fibroblasts from normal skin, different scar types, and granulation tissue has been made by transmission (TEM) and scanning electron microscopy (SEM).

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The Effect of Androgen Depletion and Replacement on the Epithelium of the Seminal Vesicle of the Aging Rat

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100116577 ◽

1975 ◽

Vol 33 ◽

pp. 590-591

Author(s):

Venita F. Allison

Keyword(s):

Cell Proliferation ◽

Seminal Vesicle ◽

Male Rats ◽

Target Cells ◽

Cell Regeneration ◽

Secretory Function ◽

Electron Microscopic ◽

Aging Rat ◽

Microscopic Studies ◽

Androgen Depletion

In 1930, Moore, Hughes and Gallager reported that after castration seminal vesicle epithelial cell atrophy occurred and that cell regeneration could be achieved with daily injections of testis extract. Electron microscopic studies have confirmed those observations and have shown that testosterone injections restore the epithelium of the seminal vesicle in adult castrated male rats. Studies concerned with the metabolism of androgens point out that dihydrotestosterone stimulates cell proliferation and that other metabolites of testosterone probably influence secretory function in certain target cells.Although the influence of androgens on adult seminal vesicle epithelial cytology is well documented, little is known of the effect of androgen depletion and replacement on those cells in aging animals. The present study is concerned with the effect of castration and testosterone injection on the epithelium of the seminal vesicle of aging rats.

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Acetaminophen: Macula densa hypersecretory activity by induced hepatotoxicity

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010012895x ◽

1987 ◽

Vol 45 ◽

pp. 934-935

Author(s):

S.S. Poolsawat ◽

C.A. Huerta ◽

S.TY. Lae ◽

G.A. Miranda

Keyword(s):

Cell Proliferation ◽

Liver Function ◽

Chronic Inflammation ◽

Foam Cell ◽

Term Effect ◽

Short Term ◽

Drug Induced ◽

Experimental Induction ◽

Tissue Alterations ◽

Toxic Responses

Introduction. Experimental induction of altered histology by chemical toxins is of particular importance if its outcome resembles histopathological phenomena. Hepatotoxic drugs and chemicals are agents that can be converted by the liver into various metabolites which consequently evoke toxic responses. Very often, these drugs are intentionally administered to resolve an illness unrelated to liver function. Because of hepatic detoxification, the resulting metabolites are suggested to be integrated into the macromolecular processes of liver function and cause an array of cellular and tissue alterations, such as increased cytoplasmic lysis, centrilobular and localized necroses, chronic inflammation and “foam cell” proliferation of the hepatic sinusoids (1-4).Most experimentally drug-induced toxicity studies have concentrated primarily on the hepatic response, frequently overlooking other physiological phenomena which are directly related to liver function. Categorically, many studies have been short-term effect investigations which seldom have followed up the complications to other tissues and organs when the liver has failed to function normally.

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