The Effects of Angiotensin Converting Enzyme Inhibitors (ACE-I) on Human N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) Levels: A Systematic Review and Meta-Analysis

Mnguni, Ayanda Trevor; Engel, Mark E; Borkum, Megan; Mayosi, Bongani M.

doi:10.1371/journal.pone.0143338

Cited by 5 publications

(7 citation statements)

References 31 publications

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“…Ac-SDKP is an ACE substrate that demonstrates meaningful anti-fibrotic effects in various experimental models of fibrotic disease ( 3 ). Ac-SDKP has been reported to inhibit cell proliferation and myofibroblast differentiation via weakening TGF-β-induced mothers against decapentaplegic homolog 2 (Smad2)/3 signaling effects ( 31 – 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide formed from its precursor, thymosin β4, released by prolyl oligopeptides ( 2 ). Ac-SDKP has antifibrosis effects and is expressed in human and animal tissues ( 3 , 4 ). The downregulation of Ac-SDKP expression is associated with organ fibrosis ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

“…Ang II is the major active protein of RAS and its fibrotic effect is primarily mediated by angiotensin II type 1 (AT1), which includes the induction of inflammatory responses as well as increased expression of transforming growth factor-β (TGF-β), proliferation of fibroblasts and extracellular matrix (ECM) deposition ( 11 – 14 ). Ac-SDKP is cleared by the N domain of ACE and its plasma and tissue levels therefore significantly increase following ACE inhibition ( 3 , 15 ). The role of ACE in producing the pro-fibrotic molecule Ang II and degrading the anti-fibrotic molecule Ac-SDKP suggests that the interaction between Ac-SDKP and RAS may be important in silicosis.…”

Section: Introductionmentioning

confidence: 99%

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Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis

et al. 2018

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N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin-angiotensin system, angiotensin-converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac-SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac-SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac-SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac-SDKP decreased. Ac-SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac-SDKP treatment had an anti-fibrotic effect in vivo. Compared with the silicosis group, the expression of α-smooth muscle actin (α-SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase-1 (MMP-1) expression and the MMP-1/tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio was increased in the Ac-SDKP treatment group. In vitro, pre-treatment with Ac-SDKP or valsartan attenuated the expression of α-SMA, Col I, Fn and AT1 in Ang II-induced fibroblasts. In addition, MMP-1 expression and the MMP-1/TIMP-1 ratio were significantly higher in Ac-SDKP and valsartan pre-treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac-SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac-SDKP protects against silicotic fibrosis by inhibiting Ang II-induced myofibroblast differentiation and extracellular matrix production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis

et al. 2018

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“…The cellular influx into the PCF is accompanied by a range of predominantly proinflammatory and pro-fibrotic mediators (e.g., interferon-γ, interleukin (IL)-10, IL-1β, IL-6, IL-8, interferon-γ induced protein, and tumor necrosis factor (TNF)), that accumulate in the pericardial fluid [14,15], and low levels of the antifibrotic tetra peptide N-acetylseryl-aspartyl-lysyl proline (AcSDKP) [16]. AcSDKP is broken down by angiotensinconverting enzyme [17], suggesting a novel role for ACE inhibitors for TBP to prevent pericardial fibrosis. Finally, recent reports suggest that among both HIV-infected and HIVuninfected patients with culture-positive pericardial fluid, Mtb bacillary loads are as high as 3.91 log 10 CFU/mL (range 0.5-8.96), with bacillary loads over 5.53 log 10 CFU/mL being significantly associated with mortality [18].…”

Section: Pathogenesismentioning

confidence: 99%

Diagnosis and Management of Tuberculous Pericarditis: What Is New?

et al. 2020

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Purpose of Review This review provides an update on the immunopathogenesis of tuberculous pericarditis (TBP), investigations to confirm tuberculous etiology, the limitations of anti-tuberculous therapy (ATT), and recent efficacy trials. Recent Findings A profibrotic immune response characterizes TBP, with low levels of AcSDKP, high levels of γ-interferon and IL-10 in the pericardium, and high levels of TGF-β and IL-10 in the blood. These findings may have implications for future therapeutic targets. Despite advances in nucleic acid amplification approaches, these tests remain disappointing for TBP. Trials of corticosteroids and colchicine have had mixed results, with no impact on mortality, evidence of a reduction in rates of constrictive pericarditis and potential harm in those with advanced HIV. Small studies suggest that ATT penetrates the pericardium poorly. Given that there is a close association between high bacillary burden and mortality, a rethink about the optimal drug doses and duration may be required. Summary The high mortality and morbidity from TBP despite use of anti-tuberculous drugs call for researches targeting hostdirected immunological determinants of treatment outcome. There is also a need for the identification of steps in clinical management where interventions are needed to improve outcomes. Keywords Tuberculous pericarditis . Mycobacterium tuberculosis Case VignetteA 33-year-old woman, HIV positive with a CD4 count of 21 cells/μL, presented with weight loss, night sweats, and shortness of breath. At presentation, recorded examination findings were temperature of 35.5°C, peripheral oxygen saturation 100%, respiratory rate 22/min, heart rate 112 beats/ min, blood pressure 106/62 mmHg with a pulsus paradoxus of 16 mmHg, and distant heart sounds. Her admission electrocardiogram (ECG), chest radiograph (CXR), and point of This article is part of the Topical Collection on Pericardial Disease

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“…These include: (I) the need to improve the rapidity and accuracy of the diagnosis of a tuberculous etiology; (II) the need to better understand the pharmacokinetics and pharmacodynamics of anti-tb drug therapy as it relates to the effectiveness of the drugs within the pericardium in patients with TB pericarditis; and (III) the need to develop strategies to reduce long-term complications of the disorder. Since those reviews the past decade has seen the publication of a significant amount of new data particularly from Sub-Saharan Africa (1,(8)(9)(10)(11)(12)(13)(14)(15)(16) designed to address some of these areas. In this focused update on the diagnosis and therapy of TBP we will review all important developments in these areas, and discuss novel interventions under exploration or with potential for future use.…”

Section: Introductionmentioning

confidence: 99%

Tuberculous pericardial disease: a focused update on diagnosis, therapy and prevention of complications

Naicker¹,

Ntsekhe²

2020

Cardiovasc Diagn Ther

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Tuberculous pericarditis (TBP) is the most important manifestation of tuberculous heart disease and is still associated with a significant morbidity and mortality in TB endemic areas. The high prevalence of the disorder over the last 3 decades has been fueled by the human immunodeficiency virus/AIDS (HIV/ AIDS) pandemic in these areas. The objective of this review is to provide a focused update on developments in the diagnosis and therapy of this condition, prevention of its complications, as well as future novel therapies. The definitive diagnosis of a tuberculous etiology in patients with suspected TBP continues to pose a challenge for clinicians. Clinical prediction scores, although never formally validated have been used with some success. However, they may be prone to both over and underdiagnosis due to lack of pericardial fluid analysis. Recent studies evaluating Xpert MTB/RIF, suggest that this advanced polymerase chain reaction (PCR) based technology does not provide increased accuracy compared to earlier iterations. However a combined two test approach starting with Xpert MTB/RIF followed by either adenosine deaminase (ADA) or interferon gamma (IFN-γ) may provide for significantly enhanced specificity and sensitivity cost permitting. Pericardiocentesis remains the gold standard for managing the compressive pericardial fluid and its adverse hemodynamic sequelae. A four drug anti-TB drug regimen at standard doses and duration is recommended. However recent evidence suggests that these drugs penetrate the pericardium very poorly potentially explaining the high mortality observed particularly in those who are culture positive with a high bacillary load. Constrictive pericarditis is the main long-term complication of TBP and is still a significant cause of heart failure in Sub-Saharan Africa. This is important because access to definitive surgical therapy where TBP is prevalent continues to be low, highlighting the need to develop strategies or interventions to prevent fibrosis and constriction. Recent detailed advanced studies of pericardial fluid in TBP have revealed a strong profibrotic transcriptomic profile, with high amounts of pro-inflammatory cytokines and low levels of the anti-fibrotic tetrapeptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP). These new insights may explain in part the high propensity to fibrosis associated with the condition and offer hope for the future use of targeted therapy to interrupt pathways and mediators of tissue damage and subsequent maladaptive healing and fibrosis. The value of effective pericardiocentesis in reducing these pro-inflammatory and profibrotic cytokines and peptides in an attempt to prevent pericardial constriction has yet to be established but has generated hypotheses for ongoing and future research.

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The Effects of Angiotensin Converting Enzyme Inhibitors (ACE-I) on Human N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) Levels: A Systematic Review and Meta-Analysis

Cited by 5 publications

References 31 publications

Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis

Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis

Diagnosis and Management of Tuberculous Pericarditis: What Is New?

Tuberculous pericardial disease: a focused update on diagnosis, therapy and prevention of complications

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