Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry

Nilsson, Anna; Fehniger, Thomas E.; Gustavsson, Lena; Andersson, Malin; Kenne, Kerstin; Marko-Varga, Gyoergy; Andrén, Per E.

doi:10.1371/journal.pone.0011411

Cited by 200 publications

(184 citation statements)

References 23 publications

(26 reference statements)

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“…The assay limit of detection was ϳ5 ng for all Ang peptides. This is similar to the approach of Nilsson et al (39) for the drug standard tiotropium.…”

Section: Methods Optimization Of Maldi Imaging For Ang Peptides In Kidsupporting

confidence: 57%

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Grobe

Elased

Cool

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Grobe N, Elased KM, Cool DR, Morris M. Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney. Am J Physiol Endocrinol Metab 302: E1016 -E1024, 2012. First published February 7, 2012 doi:10.1152/ajpendo.00515.2011.-To better understand the tissue distribution and activity of enzymes involved in angiotensin II (Ang II) processing, we developed a novel molecular imaging method using matrix-assisted laser desorption ionizationtime-of-flight (MALDI-TOF) mass spectrometry. Mouse kidney sections (12 m) were incubated with 10 -1,000 mol/l Ang II for 5-15 min at 37°C. The formed peptides Ang III and Ang-(1-7) were identified by MALDI-TOF/TOF. A third metabolite, Ang-(1-4), was generated from further degradation of Ang-(1-7). Enzymatic processing of Ang II was dose and time dependent and absent in heat-treated kidney sections. Distinct spatial distribution patterns (pseudocolor images) were observed for the peptides. Ang III was localized in renal medulla, whereas Ang-(1-7)/Ang-(1-4) was present in cortex. Regional specific peptide formation was confirmed using microdissected cortical and medullary biopsies. In vitro studies with recombinant enzymes confirmed activity of peptidases known to generate Ang III or Ang-(1-7) from Ang II: aminopeptidase A (APA), Ang-converting enzyme 2 (ACE2), prolyl carboxypeptidase (PCP), and prolyl endopeptidase (PEP). Renal medullary Ang III generation was blocked by APA inhibitor glutamate phosphonate. The ACE2 inhibitor MLN-4760 and PCP/PEP inhibitor Z-pro-prolinal reduced cortical Ang-(1-7) formation. Our results establish the power of MALDI imaging as a highly specific and information-rich analytical technique that will further aid our understanding of the role and site of Ang II processing in cardiovascular and renal pathologies. matrix-assisted laser desorption ionization imaging; angiotensin-converting enzyme 2; prolyl carboxypeptidase; prolyl endopeptidase; aminopeptidase A THE POTENT VASOCONSTRICTOR ANGIOTENSIN II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), controlling renal function and blood pressure. Inhibitors of Ang II synthesis and receptor binding are commonly used in the management of hypertension, congestive heart failure, and renal disease. However, there is growing evidence that therapeutic interventions targeting receptor binding and peptide generation have not provided as much cardiovascular risk reduction as anticipated (1, 56). The search for treatment alternatives continues, particularly since reports have emerged of novel Ang II binding sites as well as reactivation of Ang II synthesis after chronic treatment with Ang-converting enzyme (ACE) inhibitors (4, 32,41,44). Ang II degradation might be a target for potential new treatment strategies against Ang II's vasoconstrictive actions (16,42). However, this requires a reliable method to assess Ang II processing enzyme activities, particularly in pathological states shown to be associated with up/downregulation of RAS enzymes (7,15,59,61). Recognizing the ad...

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“…The assay limit of detection was ϳ5 ng for all Ang peptides. This is similar to the approach of Nilsson et al (39) for the drug standard tiotropium.…”

Section: Methods Optimization Of Maldi Imaging For Ang Peptides In Kidsupporting

confidence: 57%

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Grobe

Elased

Cool

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

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“…Few studies have quantified the dynamic range of this technique, but a recent investigation demonstrated linearity of signal intensity increasing with analyte concentration from the limit of quantitation (femtomolar) over less than 2 orders of magnitude (71). Given the relative abundance of Cter A compared with other putative cyclotide signals in leaf extract ( Fig.…”

Section: Structural and Evolutionary Implications Of The Novel Precurmentioning

confidence: 99%

Cyclotides Associate with Leaf Vasculature and Are the Products of a Novel Precursor in Petunia (Solanaceae)

Poth

Mylne

Grassl

et al. 2012

Journal of Biological Chemistry

143

139

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Background: Cyclotides are defense-related cyclic plant peptides. Results: Petunia cyclotides are encoded by novel cyclotide genes and occur in a discrete pattern in leaf architecture. Conclusion: Novel cyclotides exist in the Solanaceae and are abundant in vascular tissues. Significance: Cyclotide localization is consistent with an anti-herbivory role. Novel Solanaceae genes provide opportunities for expressing designer cyclic peptides in major crop species.

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“…6C). Tumor tissues were directly analyzed by MALDI mass spectrometry imaging (Cornett et al, 2008;Nilsson et al, 2010) for the presence and distribution of LCL124. The spatial distribution of the m/z 475.4 LCL124 in tumor tissue is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

LCL124, a Cationic Analog of Ceramide, Selectively Induces Pancreatic Cancer Cell Death by Accumulating in Mitochondria

Beckham

Lü

Jones

et al. 2012

J Pharmacol Exp Ther

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Treatment of pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic chemotherapy with gemcitabine. As the fourth leading cause of cancer-related death in the United States with dismal survival statistics, pancreatic cancer demands new and more effective treatment approaches. Resistance to gemcitabine is nearly universal and appears to involve defects in the intrinsic/ mitochondrial apoptotic pathway. The bioactive sphingolipid ceramide is a critical mediator of apoptosis initiated by a number of therapeutic modalities. It is noteworthy that insufficient ceramide accumulation has been linked to gemcitabine resistance in multiple cancer types, including pancreatic cancer.

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Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry

Cited by 200 publications

References 23 publications

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Cyclotides Associate with Leaf Vasculature and Are the Products of a Novel Precursor in Petunia (Solanaceae)

LCL124, a Cationic Analog of Ceramide, Selectively Induces Pancreatic Cancer Cell Death by Accumulating in Mitochondria

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