Up-regulation of Thrombospondin-2 in Akt1-null Mice Contributes to Compromised Tissue Repair Due to Abnormalities in Fibroblast Function

Bancroft, Tara A.; Bouaouina, Mohamed; Roberts, Sophia; Lee, Monica; Calderwood, David A.; Schwartz, Martin A.; Simons, Michael; Sessa, William C.; Kyriakides, Themis R.

doi:10.1074/jbc.m114.618421

Cited by 16 publications

(17 citation statements)

References 71 publications

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“…As has been reported by other investigators in fibroblasts 41,42 as well as in SMC in our previous publications 16, 31 , we find that transient AKT1 knockdown increases expression and activity of AKT2 in hCASMC (Fig. 4A).…”

Section: Discussionsupporting

confidence: 90%

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

Jin

Xie

Ostriker

et al. 2017

ATVB

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Objective Drug-eluting stent delivery of mTORC1 inhibitors is highly effective in preventing intimal hyperplasia following coronary revascularization, but adverse effects limit utility for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell (SMC) differentiation in an AKT2-dependent manner in vitro. Here we investigate the roles of AKT isoforms in intimal hyperplasia. Approach and Results We found that germline or smooth muscle-specific deletion of Akt2 resulted in more severe intimal hyperplasia compared to control mice after arterial denudation injury. Conversely, smooth muscle-specific Akt1 knockout prevented intimal hyperplasia, while germline Akt1 deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild type mice but had no therapeutic benefit in Akt2 knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in SMC proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced MYOCD mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4, inhibiting its binding to the MYOCD promoter. Conclusions Our data reveal opposing roles for AKT isoforms in SMC remodeling. AKT2 is required for rapamycin’s therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of myocardin (MYOCD) via FOXO4. Because AKT2 signaling is impaired in diabetes, this work has important implications for rapamycin therapy, particularly in diabetic patients.

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Section: Discussionsupporting

confidence: 90%

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

Jin

Xie

Ostriker

et al. 2017

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“…TSP2 knockout (KO) mice exhibit accelerated healing, concomitant with altered ECM and increased blood vessel density (6). Conversely, elevated TSP2 expression, as observed in Akt1 KO mice, is associated with delayed wound healing (7). Recent work has provided evidence that TSP2 expression is elevated in retina of patients with diabetes and diabetic rats (8) and endothelial progenitor cells (EPCs) in diabetic mice (9).…”

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confidence: 99%

Elevated Thrombospondin 2 Contributes to Delayed Wound Healing in Diabetes

et al. 2019

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Impaired wound healing is a major complication of diabetes and can lead to the development of chronic wounds in a significant portion of diabetes patients. Despite the risks posed by impaired healing, treatment strategies for diabetic wounds remain limited due to an incomplete understanding of the underlying pathological mechanisms. Previous studies have demonstrated that overexpression of thrombospondin‐2 (TSP2), a matricellular protein released after tissue injury, is associated with significant delays in dermal healing in various mouse models. Consistently, wounds lacking TSP2 (TSP2 KO) heal faster than wounds in wild‐type mice or mice with elevated TSP2. Thus, the present study aimed to examine the role of TSP2 in delayed healing in diabetes. First, we evaluated TSP2 expression in human wounds, and found that TSP2 is elevated in wounds from diabetes patients. Then, to determine TSP2's contribution to impaired healing in diabetes, we developed a novel diabetic TSP2 KO mouse model. Though these db/db TSP2 KO mice develop obesity and hyperglycemia comparable to db/db mice, db/db TSP2 KO mice exhibit significantly improved healing. Moreover, primary fibroblasts isolated from db/db TSP2 KO mice exhibit improved migration, providing mechanistic insight into the accelerated healing in these mice. We also studied TSP2 expression in fibroblasts, the major source of TSP2 in the wound, to explore the mechanisms leading to its overexpression in diabetes. Our results showed that TSP2 expression is increased in hyperglycemia, through increased activation of the hexosamine biosynthesis pathway and subsequent O‐GlcNAc modification of transcriptional elements. Overall, the results of this study indicate for the first time that: 1) TSP2 expression is elevated in diabetes and hyperglycemia and 2) TSP2 contributes to impaired healing in diabetes. These results represent a novel role for TSP2 in diabetes complications and a novel target for improving wound healing in diabetes. Support or Funding Information NIH HL107205, NIH GM 072194, Gruber Science Fellowship This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…4), a known inducer of both NF-jB and fibrogenic repair [34,35]. While it was not in the scope of the current studies to demonstrate that increased Thbs2 is essential for the As(III)-induced ECM remodeling, increased expression of Thbs2 is known to promote fibrosis and delay wound repair [34,35,52]. Thbs2 overexpression would also be consistent with the enhanced redox state of the muscle tissues that we have reported previ-ously [4] and may also contribute to increased oxidants and oxidant-stimulated NF-jB in both the injured and uninjured state [34,53].…”

Section: Stem Cellsmentioning

confidence: 85%

Arsenic Promotes NF-Κb-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function

et al. 2016

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Arsenic is a global health hazard that impacts over 140 million individuals worldwide. Epidemiological studies reveal prominent muscle dysfunction and mobility declines following arsenic exposure; yet, mechanisms underlying such declines are unknown. The objective of this study was to test the novel hypothesis that arsenic drives a maladaptive fibroblast phenotype to promote pathogenic myomatrix remodeling and compromise the muscle stem (satellite) cell (MuSC) niche. Mice were exposed to environmentally relevant levels of arsenic in drinking water before receiving a local muscle injury. Arsenic-exposed muscles displayed pathogenic matrix remodeling, defective myofiber regeneration and impaired functional recovery, relative to controls. When naïve human MuSCs were seeded onto three-dimensional decellularized muscle constructs derived from arsenic-exposed muscles, cells displayed an increased fibrogenic conversion and decreased myogenicity, compared with cells seeded onto control constructs. Consistent with myomatrix alterations, fibroblasts isolated from arsenic-exposed muscle displayed sustained expression of matrix remodeling genes, the majority of which were mediated by NF-κB. Inhibition of NF-κB during arsenic exposure preserved normal myofiber structure and functional recovery after injury, suggesting that NF-κB signaling serves as an important mechanism of action for the deleterious effects of arsenic on tissue healing. Taken together, the results from this study implicate myomatrix biophysical and/or biochemical characteristics as culprits in arsenic-induced MuSC dysfunction and impaired muscle regeneration. It is anticipated that these findings may aid in the development of strategies to prevent or revert the effects of arsenic on tissue healing and, more broadly, provide insight into the influence of the native myomatrix on stem cell behavior.

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Up-regulation of Thrombospondin-2 in Akt1-null Mice Contributes to Compromised Tissue Repair Due to Abnormalities in Fibroblast Function

Cited by 16 publications

References 71 publications

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

Elevated Thrombospondin 2 Contributes to Delayed Wound Healing in Diabetes

Arsenic Promotes NF-Κb-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function

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