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Article: ACE2 and TAS2R38 receptor expression in pediatric and adult patients in the nasal and oral cavity.

Franks, Zechariah G / Nandakumar, Kavitha / Santhanam, Lakshmi / Lester, Laeben / Walsh, Jonathan M / Dalesio, Nicholas M

Laryngoscope investigative otolaryngology

2024 Volume 9, Issue 1, Page(s) e1207

Abstract: Objective: To investigate differences in angiotensin-converting-enzyme-2 (ACE2) and bitter taste receptor (TAS2R38) expression between patient age groups and comorbidities to characterize the pathophysiology of coronavirus 19(COVID-19) pandemic. ACE2 is ...

Abstract	Objective: To investigate differences in angiotensin-converting-enzyme-2 (ACE2) and bitter taste receptor (TAS2R38) expression between patient age groups and comorbidities to characterize the pathophysiology of coronavirus 19(COVID-19) pandemic. ACE2 is the receptor implicated to facilitate SARS-CoV-2 infections and levels of expression may correlate to the severity of COVID-19 infection. TAS2R38 has many non-gustatory roles in disease, with some evidence of severe COVID-19 disease in certain receptor phenotypes. Methods: We conducted a prospective cohort study and collected nasal and lingual tissue from healthy pediatric ( Results: A total of 25 adult (52% male; 44% obese) and 22 pediatric (50% male; 36% obese) patients were enrolled, pediatric tissue had 43% more nasal ACE2 RNA expression than adults with a median fold change of 0.69 (IQR 0.37, 0.98) in adults and 0.99 (IQR 0.74, 1.43) in children ( Conclusions: ACE2 receptor expression is higher in nasal tissue collected from children compared to adults, suggesting COVID-19 infectivity is more complicated than ACE2 and TAS2R38 mRNA expression. Level of evidence: NA.
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article
ISSN	2378-8038
ISSN	2378-8038
DOI	10.1002/lio2.1207
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Article ; Online: An evolutionarily conserved olfactory receptor is required for sex differences in blood pressure.

Xu, Jiaojiao / Choi, Rira / Gupta, Kunal / Warren, Helen R / Santhanam, Lakshmi / Pluznick, Jennifer L

Science advances

2024 Volume 10, Issue 12, Page(s) eadk1487

Abstract: Sex differences in blood pressure are well-established, with premenopausal women having lower blood pressure than men by ~10 millimeters of mercury; however, the underlying mechanisms are not fully understood. We report here that sex differences in blood ...

Abstract	Sex differences in blood pressure are well-established, with premenopausal women having lower blood pressure than men by ~10 millimeters of mercury; however, the underlying mechanisms are not fully understood. We report here that sex differences in blood pressure are absent in olfactory receptor 558 knockout (KO) mice.
MeSH term(s)	Mice ; Animals ; Female ; Male ; Humans ; Blood Pressure/physiology ; Renin ; Receptors, Odorant/genetics ; Sex Characteristics ; Pulse Wave Analysis
Chemical Substances	Renin (EC 3.4.23.15) ; Receptors, Odorant ; Olfr558 protein, mouse
Language	English
Publishing date	2024-03-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adk1487
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Article ; Online: Lysyl oxidase like-2 in fibrosis and cardiovascular disease.

Poe, Alan / Martinez Yus, Marta / Wang, Huilei / Santhanam, Lakshmi

American journal of physiology. Cell physiology

2023 Volume 325, Issue 3, Page(s) C694–C707

Abstract: Fibrosis is an important and essential reparative response to injury that, if left uncontrolled, results in the excessive synthesis, deposition, remodeling, and stiffening of the extracellular matrix, which is deleterious to organ function. Thus, the ... ...

Abstract	Fibrosis is an important and essential reparative response to injury that, if left uncontrolled, results in the excessive synthesis, deposition, remodeling, and stiffening of the extracellular matrix, which is deleterious to organ function. Thus, the sustained activation of enzymes that catalyze matrix remodeling and cross linking is a fundamental step in the pathology of fibrotic diseases. Recent studies have implicated the amine oxidase lysyl oxidase like-2 (LOXL2) in this process and established significantly elevated expression of LOXL2 as a key component of profibrotic conditions in several organ systems. Understanding the relationship between LOXL2 and fibrosis as well as the mechanisms behind these relationships can offer significant insights for developing novel therapies. Here, we summarize the key findings that demonstrate the link between LOXL2 and fibrosis and inflammation, examine current therapeutics targeting LOXL2 for the treatment of fibrosis, and discuss future directions for experiments and biomedical engineering.
MeSH term(s)	Humans ; Protein-Lysine 6-Oxidase/genetics ; Cardiovascular Diseases/genetics ; Fibrosis ; Extracellular Matrix
Chemical Substances	Protein-Lysine 6-Oxidase (EC 1.4.3.13)
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00176.2023
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Article: Editorial: Cardiovascular Remodeling in Aging and Disease.

Steppan, Jochen / Nyhan, Daniel / Santhanam, Lakshmi

Frontiers in physiology

2022 Volume 13, Page(s) 867185

Language	English
Publishing date	2022-03-07
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.867185
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Article: Vascular stiffening in aging females with a hypertension-induced HIF2A gain-of-function mutation.

Volkova, Eugenia / Procell, Linda / Kong, Lingyang / Santhanam, Lakshmi / Gerecht, Sharon

Bioengineering & translational medicine

2022 Volume 8, Issue 2, Page(s) e10403

Abstract: Pulmonary arterial hypertension (PAH) is more prevalent in females than males; the causes of this sex difference have not been adequately explored. Gain-of-function (GOF) mutations in hypoxia-inducible factor 2α (HIF2A) lead to PAH and thrombotic ... ...

Abstract	Pulmonary arterial hypertension (PAH) is more prevalent in females than males; the causes of this sex difference have not been adequately explored. Gain-of-function (GOF) mutations in hypoxia-inducible factor 2α (HIF2A) lead to PAH and thrombotic consequences in patients and mice. Additionally, multiple emerging studies suggest that elevated systemic arterial stiffening (SAS) occurs in PAH; this could have critical prognostic value. Here, we utilized a HIF2A GOF mouse model to determine how SAS can be used as a prognosticator in sex-divergent PAH. We analyzed survival, vascular mechanics, and vascular phenotypes in young adult (8-16 weeks) and middle age (9-12 months) Hif2a GOF mice. We find that Hif2a heterozygous (HT) female mice, but not Hif2a HT male mice, exhibit poor survival, SAS upon aging, and decreased ability to withstand repeated physiological strain. Hif2a HT female mice also display thickening of the adventitial intima and increased collagen I and collagen III in all layers of the thoracic aorta. Our findings demonstrate differing PAH progression in female and male Hif2a GOF mice. Specifically, alterations in extracellular matrix (ECM) content led to vascular stiffening in aged females, resulting in poor survival. Moreover, we show that SAS emerges early in mice with PAH by coupling studies of vascular mechanics and analyzing vascular structure and composition. Importantly, we present a model for assessing sex differences in hereditary PAH progression and sex-specific prognosis, proposing that aortic stiffening can be used to prognosticate future poor outcomes in PAH.
Language	English
Publishing date	2022-10-03
Publishing country	United States
Document type	Journal Article
ISSN	2380-6761
ISSN	2380-6761
DOI	10.1002/btm2.10403
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Article ; Online: Optimization of resting tension for wire myography in male rat pulmonary arteries.

Choi, Rira / Narayanan, Roshini / Jandu, Sandeep / Savage, William / Kang, Sara / Wodu, Bulouere / Nandakumar, Kavitha / Santhanam, Lakshmi / Steppan, Jochen

Physiological reports

2024 Volume 12, Issue 1, Page(s) e15911

Abstract: Wire myography to test vasomotor functions of blood vessels ex-vivo are well-established for the systemic circulation, however, there is no consensus on protocols for pulmonary arteries. We created a standardized wire myography protocol for healthy rat ... ...

Abstract	Wire myography to test vasomotor functions of blood vessels ex-vivo are well-established for the systemic circulation, however, there is no consensus on protocols for pulmonary arteries. We created a standardized wire myography protocol for healthy rat PAs and validated this in a pulmonary hypertension (PH) model. Vessels stretched to higher initial tensions (5.0, 7.5 and 10.0 mN) exhibited a uniform response to phenylephrine, a larger dynamic range, and lower EC50 values. The endothelium-mediated relaxation showed that moderate tensions (7.5 and 10.0 mN) produced robust responses with higher maximum relaxation and lower EC50 values. For endothelium independent responses, the higher initial tension groups had lower and more consistent EC50 values than the lower initial tension groups. Pulmonary arteries from rats with PH were more responsive to vasoactive drugs when subjected to a higher initial tension. Notably, vessels in the PH group subjected to 15.0 mN exhibited high dynamic ranges in contractile and relaxation responses without tearing. Lastly, we observed attenuated cholinergic responses in these vessels-consistent with endothelial dysfunction in PH. Therefore, a moderate initial tension of 7.5-10.0 mN is optimal for healthy rat pulmonary arteries and a higher initial tension of 15.0 mN is optimal for pulmonary arteries from animals with PH.
MeSH term(s)	Rats ; Male ; Animals ; Pulmonary Artery ; Phenylephrine ; Hypertension, Pulmonary ; Myography/methods ; Vasodilation
Chemical Substances	Phenylephrine (1WS297W6MV)
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.15911
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Article ; Online: Lysyl oxidase-like 2 processing by factor Xa modulates its activity and substrate preference.

Wang, Huilei / Poe, Alan / Martinez Yus, Marta / Pak, Lydia / Nandakumar, Kavitha / Santhanam, Lakshmi

Communications biology

2023 Volume 6, Issue 1, Page(s) 375

Abstract: Lysyl oxidase-like 2 (LOXL2) has been identified as an essential mediator of extracellular matrix (ECM) remodeling in several disease processes including cardiovascular disease. Thus, there is growing interest in understanding the mechanisms by which ... ...

Abstract	Lysyl oxidase-like 2 (LOXL2) has been identified as an essential mediator of extracellular matrix (ECM) remodeling in several disease processes including cardiovascular disease. Thus, there is growing interest in understanding the mechanisms by which LOXL2 is regulated in cells and tissue. While LOXL2 occurs both in full length and processed forms in cells and tissue, the precise identity of the proteases that process LOXL2 and the consequences of processing on LOXL2's function remain incompletely understood. Here we show that Factor Xa (FXa) is a protease that processes LOXL2 at Arg-338. Processing by FXa does not affect the enzymatic activity of soluble LOXL2. However, in situ in vascular smooth muscle cells, LOXL2 processing by FXa results in decreased cross-linking activity in the ECM and shifts substrate preference of LOXL2 from type IV collagen to type I collagen. Additionally, processing by FXa increases the interactions between LOXL2 and prototypical LOX, suggesting a potential compensatory mechanism to preserve total LOXs activity in the vascular ECM. FXa expression is prevalent in various organ systems and shares similar roles in fibrotic disease progression as LOXL2. Thus, LOXL2 processing by FXa could have significant implications in pathologies where LOXL2 is involved.
MeSH term(s)	Protein-Lysine 6-Oxidase/metabolism ; Factor Xa/metabolism ; Extracellular Matrix/metabolism ; Myocytes, Smooth Muscle/metabolism
Chemical Substances	Protein-Lysine 6-Oxidase (EC 1.4.3.13) ; Factor Xa (EC 3.4.21.6)
Language	English
Publishing date	2023-04-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04748-8
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Article: Assessing Renal Microvascular Reactivity by Laser Speckle-Contrast Imaging in Angiotensin-II-Treated Mice.

Mottard, Nicolas / Berkowitz, Dan E / Santhanam, Lakshmi

International journal of nephrology and renovascular disease

2020 Volume 13, Page(s) 45–51

Abstract: Introduction: The kidney is one of the main organs affected by microvascular damage wrought by hypertension. We developed an approach to investigate renal microcirculatory disturbance in live mice by measuring post-occlusive reactive hyperemia (PORH), a ...

Abstract	Introduction: The kidney is one of the main organs affected by microvascular damage wrought by hypertension. We developed an approach to investigate renal microcirculatory disturbance in live mice by measuring post-occlusive reactive hyperemia (PORH), a reactivity test exploring endothelial and neuro-microvascular functioning. Laser speckle-contrast analysis (LASCA) assesses microvascular blood flow; it provides real-time images of spatial and temporal blood flow dynamics. We compared basal blood flow and PORH test between control and angiotensin-II-treated mice (Ang-II) to validate the model. Objective: The study objective was to develop an approach to investigate renal microcirculation, and then to compare microvascular reactivity assessed on LASCA in control versus Ang-II mice. Methods: Thirty 7-week-old wild-type C57BL/6J mice were allocated into two groups. One received angiotensin-II via osmotic minipumps (Ang-II; n=15); the other served as control (n=15). Basal blood flow was measured on LASCA. The PORH test was then performed in the two groups. Results: Control mice had significantly lower basal renal microcirculatory flow, expressed in perfusion units (PU), than Ang-II-treated mice (1448 ± 96 vs 1703 ± 185 PU, respectively; P < 0.05). Peak flow was lower in controls than in Ang-II mice (1617±104 vs.1724 ± 205 PU, respectively; P=0.21). Control mice had significantly higher kidney PORH than Ang-II mice (8±3 vs 1±4%, respectively; P < 0.05). Conclusion: We developed an innovative technique to study renal microcirculation in mice. Ang-II-treated mice showed significantly higher basal blood flow than controls, while PORH was significantly higher in controls than in Ang-II mice.
Language	English
Publishing date	2020-03-27
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2508160-3
ISSN	1178-7058
ISSN	1178-7058
DOI	10.2147/IJNRD.S240147
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Article ; Online: Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging.

Löser, Reik / Kuchar, Manuela / Wodtke, Robert / Neuber, Christin / Belter, Birgit / Kopka, Klaus / Santhanam, Lakshmi / Pietzsch, Jens

ChemMedChem

2023 Volume 18, Issue 18, Page(s) e202300331

Abstract: The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl ... ...

Abstract	The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure-activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.
MeSH term(s)	Humans ; Protein-Lysine 6-Oxidase/therapeutic use ; Neoplasms/diagnostic imaging ; Neoplasms/drug therapy ; Fibrosis ; Fibroblasts ; Diagnostic Imaging ; Tumor Microenvironment
Chemical Substances	Protein-Lysine 6-Oxidase (EC 1.4.3.13)
Language	English
Publishing date	2023-09-04
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202300331
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Zs.A 6280: Show issues

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Article: Pressure-based estimation of right ventricular ejection fraction: Validation as a clinically relevant target for drug development in a rodent model of pulmonary hypertension

Elassal, Ahmed / Steppan, Jochen / Charania, Sofia / Santhanam, Lakshmi / Singh, Inderjit / Heerdt, Paul M.

Journal of pharmacological and toxicological methods. 2021 Nov., Dec., v. 112

2021

Abstract: Depressed right ventricular ejection fraction (RVEF) has clear prognostic significance in patients with pulmonary arterial hypertension (PAH). Accordingly, improvements in RVEF represent a desirable end-point in the development of PAH therapies. However, ...

Abstract	Depressed right ventricular ejection fraction (RVEF) has clear prognostic significance in patients with pulmonary arterial hypertension (PAH). Accordingly, improvements in RVEF represent a desirable end-point in the development of PAH therapies. However, current methods for determination of RVEF require measurement of RV volume and are relatively complex and costly. Here, we validate a novel method for quantitative estimation of RVEF in rats based entirely upon analysis of readily available RV pressure waveforms that eliminates the need for simultaneous volume measurement and can be rapidly applied.Right ventricular pressure and volume (conductance catheter) measurements acquired from 15 rats (7 controls, 8 sugen/hypoxia PAH; 220–250 g) were used for the study. Over the same 10 beat interval, RVEF was directly measured from the volume signal and estimated from the pressure signal. Simultaneous measures were compared by linear regression and Bland-Altman analysis to define bias (accuracy) and precision.Measured RVEF ranged from 0.19 to 0.60 (mean 0.44 ± 0.10) and estimated from 0.19 to 0.52 (mean 0.42 ± 0.09). Across the dataset there was strong correlation (r² = 0.813), with minimal bias (0.01) and an overall error of 20% consistent with acceptable accuracy and precision.Study results support the potential utility of a method based entirely upon analysis of the RV pressure waveform for assessing drug effects on RVEF in rat models of PAH.
Keywords	animal models ; catheters ; data collection ; drug development ; drugs ; hypertension ; hypoxia ; pulmonary artery ; rats ; regression analysis ; toxicology
Language	English
Dates of publication	2021-11
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/j.vascn.2021.107102
Database	NAL-Catalogue (AGRICOLA)

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