Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy

Bellumkonda, Lavanya; Patel, Jignesh

doi:10.1111/ctr.13769

Cited by 12 publications

(5 citation statements)

References 46 publications

(60 reference statements)

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“…Osteogenic markers such as osteopontin or alkaline phosphatase in contrast, seem to be in general rather downregulated by rapamycin as it has been shown for VIC ( 48 ) as well as for vascular smooth muscle cells ( 52 ). Discrepancies between our findings of unchanged OPN gene expression and an increased ALP activity and reports on downregulation of these markers might therefore be due to different treatment durations, an issue that is also discussed in the clinical application of mTOR inhibitors ( 54 ). Taken together, in our setting, rapamycin treatment leads to an activation of VIC together with an upregulation of ALP activity.…”

Section: Discussioncontrasting

confidence: 54%

Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling

Selig

Krug²,

Küppers³

et al. 2022

Front. Cardiovasc. Med.

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Diabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvular interstitial cells (VIC) display canonical elements of classical insulin signaling and develop insulin resistance upon hyperinsulinemia and hyperglycemia accompanied by impaired glucose metabolism. Analyses of cultured VIC and aortic valve tissue revealed extracellular matrix remodeling and degenerative processes. Since PI3K signaling through mammalian target of rapamycin (mTOR) is involved in fibrotic processes of the heart, we aim at further functional investigation of this particular Akt-downstream signaling pathway in the context of diabetes-induced CAVD. Primary cultures of VIC were treated with hyperinsulinemia and hyperglycemia. Phosphorylation of mTOR(Ser2448) was determined by Western blot analysis after acute insulin stimulus. Inhibition of mTOR phosphorylation was performed by rapamycin. Phosphorylation of mTOR complex 1 (MTORC1) downstream substrates 4E-BP1(Thr37/46) and P70S6K(Thr389), and MTORC2 downstream substrate Akt(Ser473) as well as the PDK1-dependent phosphorylation of Akt(Thr308) was investigated. Markers for extracellular matrix remodeling, cell differentiation and degenerative changes were analyzed by Western blot analysis, semi-quantitative real-time PCR and colorimetric assays. Hyperinsulinemia and hyperglycemia lead to alterations of VIC activation, differentiation and matrix remodeling as well as to an abrogation of mTOR phosphorylation. Inhibition of mTOR signaling by rapamycin leads to a general downregulation of matrix molecules, but to an upregulation of α-smooth muscle actin expression and alkaline phosphatase activity. Comparison of expression patterns upon diabetic conditions and rapamycin treatment reveal a possible regulation of particular matrix components and key degeneration markers by MTORC1 downstream signaling. The present findings broaden the understanding of mitogenic signaling pathways in VIC triggered by hyperinsulinemia and hyperglycemia, supporting the quest for developing strategies of prevention and tailored treatment of CAVD in diabetic patients.

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Section: Discussioncontrasting

confidence: 54%

Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling

Selig

Krug²,

Küppers³

et al. 2022

Front. Cardiovasc. Med.

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“…48 A number of drugs in widespread use to treat graft rejection modulate metabolism in immune cells that play a key role in trained innate immunity. [105][106][107] Therefore, there is a need to fully understand the extent to which these inhibitors play a role in innate immune cellmediated transplantation rejection and tolerance.…”

Section: Strategies That Target Trained Immunity For Improving Transp...mentioning

confidence: 99%

Trained Innate Immunity in Hematopoietic Stem Cell and Solid Organ Transplantation

Cunningham

Mills

2021

Transplantation

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Although significant progress has been made to improve short-term survival of transplant patients, long-term acceptance of allografts in solid organ and hematopoietic stem cell (HSC) transplantation is still a significant challenge. Current therapeutics for preventing or treating allograft rejection rely on potent immunosuppressive drugs that primarily target T cells of the adaptive immune response. Promising advances in transplant immunology have highlighted the importance of innate immune responses in allograft acceptance and rejection. Recent studies have demonstrated that innate immune cells are capable of mediating memory-like responses during inflammation, a term known as trained innate immunity. In this process, innate immune cells, such as macrophages and monocytes, undergo metabolic and epigenetic changes in response to a primary stimulus with a pathogen or their products that result in faster and more robust responses to a secondary stimulus. There is also some evidence to suggest that innate immune cells or their progenitors may be more anti-inflammatory after initial stimulation with appropriate agents, such as helminth products. Although this phenomenon has primarily been studied in the context of infection, there is emerging evidence to suggest that it could play a vital role in transplantation rejection and tolerance. Mechanisms of training innate immune cells and their progenitors in the bone marrow are therefore attractive targets for mediating long-term solid organ and HSC transplant tolerance. In this review, we highlight the potential role of proinflammatory and anti-inflammatory mechanisms of trained innate immunity in solid organ and HSC transplantation.

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“…CAV is a progressive disease affecting arterial and venous vascular beds. Immune mediated endothelial injury leads to progressive fibroproliferative disease in which vascular smooth muscle cells (VSMC) and intimal hyperplasia leads to diffuse luminal obstruction 1 . While immune mediated injury initiates the process, non‐immune mechanisms can contribute to progression of the disease process.…”

Section: Introductionmentioning

confidence: 99%

“…It is reported in around 30% of heart transplant recipients by 5 years and close to 50% by 10 years 2 . The International Society of Heart and Lung Transplantation (ISHLT) has divided CAV into grades CAV 0‐3 and the 5‐year mortality or need for retransplantation ranges from 7‐50% based on the degree of CAV 1 . CAV is the leading cause of death beyond 3 years post transplantation.…”

Section: Introductionmentioning

confidence: 99%

Role of ascorbic acid in cardiac allograft vasculopathy

Chang,

Martin,

Colvin

et al. 2023

Clinical Transplantation

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Purpose of the ReviewCardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long‐term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post‐transplant care.Recent DataRecent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial.SummaryCAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large‐scale randomized control studies of ascorbic acid are needed to establish the role in routine post‐transplant management.

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Recent advances in the role of mammalian target of rapamycin inhibitors on cardiac allograft vasculopathy

Cited by 12 publications

References 46 publications

Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling

Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling

Trained Innate Immunity in Hematopoietic Stem Cell and Solid Organ Transplantation

Role of ascorbic acid in cardiac allograft vasculopathy

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