Mevastatin promotes healing by targeting caveolin-1 to restore EGFR signaling

Sawaya, Andrew P.; Jozic, Ivan; Stone, Rivka C.; Pastar, Irena; Egger, Andjela; Stojadinović, Olivera; Glinos, George D.; Kirsner, Robert S.; Tomic‐Canic, Marjana

doi:10.1172/jci.insight.129320

Cited by 39 publications

(43 citation statements)

References 47 publications

(62 reference statements)

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“…Some mechanistic investigations at cellular level have shown that mevastatin switches human keratinocytes from a hyperproliferative to a promigratory phenotype, by modulating EGF signaling and stimulating cytoskeletal reorganization and lamellipodia formation. These effects were observed also in biopsies from diabetic foot ulcer patients strengthening the possible use of a topical statin in the treatment of diabetic ulcers [60]. In a porcine wound model, topically applied mevastatin improved epithelization and angiogenesis by contrasting cortisol and FPP actions.…”

Section: Statinsmentioning

confidence: 70%

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

et al. 2020

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Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.

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Section: Statinsmentioning

confidence: 70%

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

et al. 2020

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“…We have previously shown that Cav1 localizes to the basal layer epidermal keratinocytes where it antagonizes keratinocyte migration and proliferation. Subsequently, spatiotemporal downregulation of Cav1 is required for appropriate cutaneous wound healing, and topical formulations which perturb Cav1 can accelerate wound closure using in vitro human skin organ cultures, human ex vivo wounds, as well as both murine and porcine in vivo wounds [ 55 , 56 ]. Given that eHFSCs critically participate in later stages of cutaneous wound healing (e.g., by producing progenitor cells that migrate out of the bulge into the epidermis to facilitate re-epithelialization [ 61 , 62 , 63 ]), and the fact that Cav1 downregulation is required for wound closure [ 55 , 56 ], the role of Cav1 might extend to epithelial HF progenitor cells and their emigration into the epidermis.…”

Section: Premisesmentioning

confidence: 99%

“…[ 49 , 54 ]. Although a few recent studies have begun to characterize expression and the potential functional role of Cav1 in skin epithelium [ 50 , 55 , 56 , 57 , 58 , 59 , 60 ], its role in human hair physiology remains entirely unknown. Here, we argue that Cav1 deserves special scrutiny and therapeutic targeting in future PLCA management, namely in the treatment of FFA.…”

Section: Introductionmentioning

confidence: 99%

A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia?

et al. 2021

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Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-β and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.

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“…[56] Interestingly, we observed that Cav1 can be used as a bona of migration and resulted in accelerated wound closure. [56,197] However, it is yet to be established whether the same is true for pressure ulcers.…”

Section: Role Of C Av1 In Cellul Ar S Ene Scen Ce and S K In Ag Eingmentioning

confidence: 99%

“…Upregulation of Cav1, as seen in non‐healing chronic wounds (diabetic foot ulcers and venous leg ulcers), results in increased Cav1 interaction with membranous glucocorticoid receptor (which potentiates wound healing‐inhibitory signalling events), as well as sequestration of EGFR signalling, which altogether results in inhibition of keratinocyte migration and subsequent wound closure. Interestingly, topical administration of cholesterol depleting agents, including (MβCD and Mevasatin), reversed the Cav1‐mediated inhibition of migration and resulted in accelerated wound closure . However, it is yet to be established whether the same is true for pressure ulcers.…”

Section: Role Of Cav1 In Wound Healingmentioning

confidence: 99%

The importance of caveolins and caveolae to dermatology: Lessons from the caves and beyond

Egger

Rajabi‐Estarabadi

Williams

et al. 2020

Experimental Dermatology

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Caveolae are flask‐shaped invaginations of the cell membrane rich in cholesterol and sphingomyelin, with caveolin proteins acting as their primary structural components that allow compartmentalization and orchestration of various signalling molecules. In this review, we discuss how pleiotropic functions of caveolin‐1 (Cav1) and its intricate roles in numerous cellular functions including lipid trafficking, signalling, cell migration and proliferation, as well as cellular senescence, infection and inflammation, are integral for normal development and functioning of skin and its appendages. We then examine how disruption of the homeostatic levels of Cav1 can lead to development of various cutaneous pathophysiologies including skin cancers, cutaneous fibroses, psoriasis, alopecia, age‐related changes in skin and aberrant wound healing and propose how levels of Cav1 may have theragnostic value in skin physiology/pathophysiology.

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Mevastatin promotes healing by targeting caveolin-1 to restore EGFR signaling

Cited by 39 publications

References 47 publications

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia?

The importance of caveolins and caveolae to dermatology: Lessons from the caves and beyond

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