Prevention of transplant coronary artery disease by prenylation inhibitors

Stein, William; Schrepfer, Sonja; Itoh, Satoshi; Kimura, Naoyuki; Velotta, Jeffrey B.; Palmer, Owen P.; Bartos, Jason A.; Wang, Xi; Robbins, Robert C.; Fischbein, Michael P.

doi:10.1016/j.healun.2011.01.720

Cited by 11 publications

(2 citation statements)

References 37 publications

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“…7 , 8 ). These results are in line with previous studies that FTase inhibitors elicit anti-inflammatory action in non-immune cells under pathophysiological conditions [ 52 – 54 ]. Inflammation can be both adaptive and detrimental, but excessive inflammatory response is associated with the worse clinical outcome in many cases of major trauma, including burn injury [ 55 ].…”

Section: Discussionsupporting

confidence: 93%

Role of Protein Farnesylation in Burn-Induced Metabolic Derangements and Insulin Resistance in Mouse Skeletal Muscle

et al. 2015

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ObjectiveMetabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury) and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase) inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle.MethodsA full thickness burn (30% total body surface area) was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP) or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated.ResultsBurn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR), insulin receptor substrate (IRS)-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling), PTEN (a negative regulator of Akt-mediated signaling), protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277.ConclusionsOur data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a pivotal role in burn-induced metabolic dysfunction and inflammatory response. Our study identifies FTase as a novel potential molecular target to reverse or ameliorate metabolic derangements in burn patients.

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Section: Discussionsupporting

confidence: 93%

Role of Protein Farnesylation in Burn-Induced Metabolic Derangements and Insulin Resistance in Mouse Skeletal Muscle

et al. 2015

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“…The downstream products, farnesyl pyrophosphate and geranyl pyrophosphate, are lipid moieties that can modulate the function of certain essential signaling proteins that influence smooth muscle cells and the generation of nitric oxide (NO) [22]. Statins reduce matrix metalloproteinase secretion and SMC migration and proliferation, and the effect on SMCs may be the major mechanism by which statins decrease the development of CAV [23,24]. Statins also block activation of T-cells and natural killer (NK) cells by repressing interferon-gamma induced MHC-II expression [25].…”

Section: Statinsmentioning

confidence: 99%

Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

Gupta¹

2014

Cardiol Pharmacol

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Cardiac allograft vasculopathy (CAV) of heart transplants is responsible for up to one-third of deaths at 5 years following cardiac transplantation. Risk factors for CAV include both traditional risk factors and immune factors. Drugs used for prevention and treatment of CAV include statins, calcium channel blockers and immunosuppressive agents. This review discusses the currently available drugs for CAV, the evidence behind their use, and future targets of therapy.

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