المؤلفون: Zechariah G. Franks, Kavitha Nandakumar, Lakshmi Santhanam, Laeben Lester, Jonathan M. Walsh, Nicholas M. Dalesio

المصدر: Laryngoscope Investigative Otolaryngology, Vol 9, Iss 1, Pp n/a-n/a (2024)

مصطلحات موضوعية: ACE2, bitter taste receptor, coronavirus, COVID‐19, obesity, Otorhinolaryngology, RF1-547, Surgery, RD1-811

الوصف: 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 (n = 22) and adult (n = 25) patients undergoing general anesthesia for elective procedures. RNA isolation and qPCR were performed with primers targeting ACE2 and TAS2R38. 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 (p

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2378-8038Test

الوصول الحر: https://doaj.org/article/21bd9c81a96f425592488d0f950acd9cTest

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

المصدر: Physiological Reports, Vol 12, Iss 1, Pp n/a-n/a (2024)

مصطلحات موضوعية: protocol, pulmonary arterial hypertension, pulmonary hypertension, remodeling, vascular stiffness, wire myography, Physiology, QP1-981

الوصف: 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.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2051-817XTest

الوصول الحر: https://doaj.org/article/4a8feeadd1064cd6865d1f8f01335e90Test

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

المصدر: Communications Biology, Vol 6, Iss 1, Pp 1-12 (2023)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: A role for Factor Xa in the proteolytic processing of LOXL2 is identified and the resulting processed LOXL2 changes affinity from collagen IV to collagen I and increasingly binds to LOX, suggesting that LOX could be recruited to the regions where cleaved LOXL2 is deposited.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2399-3642Test

الوصول الحر: https://doaj.org/article/db0c8591b96e48039068fa7208b99719Test

المؤلفون: Kei Akiyoshi, Tomonari Fujimori, Xiuping Fu, Aparna P. Shah, Atsushi Yamaguchi, Charles Steenbergen, Lakshmi Santhanam, Dan Berkowitz, Eric Tuday, Jay M. Baraban, Samarjit Das

المصدر: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 12, Iss 14 (2023)

مصطلحات موضوعية: adenosine A2A receptor, microRNA, microRNA‐181b, microRNA degradation, translin/trax, vascular stiffness, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Background The identification of large‐artery stiffness as a major, independent risk factor for cardiovascular disease–associated morbidity and death has focused attention on identifying therapeutic strategies to combat this disorder. Genetic manipulations that delete or inactivate the translin/trax microRNA‐degrading enzyme confer protection against aortic stiffness induced by chronic ingestion of high‐salt water (4%NaCl in drinking water for 3 weeks) or associated with aging. Therefore, there is heightened interest in identifying interventions capable of inhibiting translin/trax RNase activity, as these may have therapeutic efficacy in large‐artery stiffness. Methods and Results Activation of neuronal adenosine A2A receptors (A2ARs) triggers dissociation of trax from its C‐terminus. As A2ARs are expressed by vascular smooth muscle cells (VSMCs), we investigated whether stimulation of A2AR on vascular smooth muscle cells promotes the association of translin with trax and, thereby increases translin/trax complex activity. We found that treatment of A7r5 cells with the A2AR agonist CGS21680 leads to increased association of trax with translin. Furthermore, this treatment decreases levels of pre‐microRNA‐181b, a target of translin/trax, and those of its downstream product, mature microRNA‐181b. To check whether A2AR activation might contribute to high‐salt water–induced aortic stiffening, we assessed the impact of daily treatment with the selective A2AR antagonist SCH58261 in this paradigm. We found that this treatment blocked aortic stiffening induced by high‐salt water. Further, we confirmed that the age‐associated decline in aortic pre‐microRNA‐181b/microRNA‐181b levels observed in mice also occurs in humans. Conclusions These findings suggest that further studies are warranted to evaluate whether blockade of A2ARs may have therapeutic potential in treating large‐artery stiffness.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2047-9980Test

الوصول الحر: https://doaj.org/article/a71419da408847be91b663d9bf83fc75Test

المؤلفون: Jochen Steppan, Kavitha Nandakumar, Huilei Wang, Rosie Jang, Logan Smith, Sara Kang, William Savage, Maria Bauer, Rira Choi, Travis Brady, Bulouere Princess Wodu, Susanna Scafidi, Joseph Scafidi, Lakshmi Santhanam

المصدر: Physiological Reports, Vol 11, Iss 7, Pp n/a-n/a (2023)

مصطلحات موضوعية: arterial aging, lysyl oxidase, matrix remodeling, neonatal hypoxia, Physiology, QP1-981

الوصف: Abstract Hypoxia in the neonatal period is associated with early manifestations of adverse cardiovascular health in adulthood including higher risk of hypertension and atherosclerosis. We hypothesize that this occurs due to activation of lysyl oxidases (LOXs) and the remodeling of the large conduit vessels, leading to early arterial stiffening. Newborn C57Bl/6 mice were exposed to hypoxia (FiO2 = 11.5%) from postnatal day 1 (P1) to postnatal day 11 (P11), followed by resumption of normoxia. Controls were maintained in normoxia. Using in vivo (pulse wave velocity; PWV) and ex vivo (tensile testing) arterial stiffness indexes, we determined that mice exposed to neonatal hypoxia had significantly higher arterial stiffness compared with normoxia controls by young adulthood (P60), and it increased further by P120. Echocardiography performed at P60 showed that mice exposed to hypoxia displayed a compensated dilated cardiomyopathy. Western blotting revelated that neonatal hypoxia accelerated age‐related increase in LOXL2 protein expression in the aorta and elevated LOXL2 expression in the PA at P11 with a delayed decay toward normoxic controls. In the heart and lung, gene and protein expression of LOX/LOXL2 were upregulated at P11, with a delayed decay when compared to normoxic controls. Neonatal hypoxia results in a significant increase in arterial stiffness in early adulthood due to aberrant LOX/LOXL2 expression. This suggests an acceleration in the mechanical decline of the cardiovascular system, that contributes to increased risk of hypertension in young adults exposed to neonatal hypoxia that may increase susceptibility to further insults.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2051-817XTest

الوصول الحر: https://doaj.org/article/9fe5f4f1fd4f4d71968c9b6b4ce21315Test

المؤلفون: Eugenia Volkova, Linda Procell, Lingyang Kong, Lakshmi Santhanam, Sharon Gerecht

المصدر: Bioengineering & Translational Medicine, Vol 8, Iss 2, Pp n/a-n/a (2023)

مصطلحات موضوعية: Arterial Stiffening, Extracellular Matrix, HIF, HIF2a, Hypertension, Hypoxia, Chemical engineering, TP155-156, Biotechnology, TP248.13-248.65, Therapeutics. Pharmacology, RM1-950

الوصف: 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.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2380-6761Test

الوصول الحر: https://doaj.org/article/31d97831abae4b3caf2516ac6c24b8fbTest

المؤلفون: Nicolas Philip, Hongyang Pi, Mahin Gadkari, Xin Yun, John Huetsch, Cissy Zhang, Robert Harlan, Aurelie Roux, David Graham, Larissa Shimoda, Anne Le, Scott Visovatti, Peter J. Leary, Sina A. Gharib, Catherine Simpson, Lakshmi Santhanam, Jochen Steppan, Karthik Suresh

المصدر: Pulmonary Circulation, Vol 13, Iss 1, Pp n/a-n/a (2023)

مصطلحات موضوعية: amino acid metabolism, endothelial cells, metabolomics, PAH, Diseases of the circulatory (Cardiovascular) system, RC666-701, Diseases of the respiratory system, RC705-779

الوصف: Abstract In pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation. In this study, we utilize the sugen/hypoxia (SuHx) rodent model of PAH to examine the RV, LV and MVEC intracellular metabolome (using targeted metabolomics) in normoxic and SuHx rats. We additionally validate key findings from our metabolomics experiments with data obtained from cell culture of normoxic and SuHx MVECs, as well as metabolomics of human serum samples from two different PAH patient cohorts. Taken together, our data, spanning rat serum, human serum and primary isolated rat MVECs reveal that: (1) key classes of amino acids (specifically, branched chain amino acids—BCAA) are lower in the pre‐capillary (i.e., RV) serum of SuHx rats (and humans); (2) intracellular amino acid levels (in particular BCAAs) are increased in SuHx‐MVECs; (3) there may be secretion rather than utilization of amino acids across the pulmonary microvasculature in PAH and (4) an oxidized glutathione gradient is present across the pulmonary vasculature, suggesting a novel fate for increased glutamine uptake (i.e., as a source of glutathione). in MVECs in PAH. In summary, these data reveal new insight into the shifts in amino acid metabolism occurring across the pulmonary circulation in PAH.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-8940Test

الوصول الحر: https://doaj.org/article/97025afab3c44d04bea6835abb15b53eTest

المؤلفون: Huilei Wang, James Chen, Sandeep Jandu, Sean Melucci, William Savage, Kavitha Nandakumar, Sara K. Kang, Sebastian Barreto-Ortiz, Alan Poe, Shivam Rastogi, Maria Bauer, Jochen Steppan, Lakshmi Santhanam

المصدر: Cell Death Discovery, Vol 7, Iss 1, Pp 1-12 (2021)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671

الوصف: Abstract Tissue transglutaminase (TG2), a multifunctional protein of the transglutaminase family, has putative transamidation-independent functions in aging-associated vascular stiffening and dysfunction. Developing preclinical models will be critical to fully understand the physiologic relevance of TG2’s transamidation-independent activity and to identify the specific function of TG2 for therapeutic targeting. Therefore, in this study, we harnessed CRISPR-Cas9 gene editing technology to introduce a mutation at cysteine 277 in the active site of the mouse Tgm2 gene. Heterozygous and homozygous Tgm2-C277S mice were phenotypically normal and were born at the expected Mendelian frequency. TG2 protein was ubiquitously expressed in the Tgm2-C277S mice at levels similar to those of wild-type (WT) mice. In the Tgm2-C277S mice, TG2 transglutaminase function was successfully obliterated, but the transamidation-independent functions ascribed to GTP, fibronectin, and integrin binding were preserved. In vitro, a remodeling stimulus led to the significant loss of vascular compliance in WT mice, but not in the Tgm2-C277S or TG2−/− mice. Vascular stiffness increased with age in WT mice, as measured by pulse-wave velocity and tensile testing. Tgm2-C277S mice were protected from age-associated vascular stiffening, and TG2 knockout yielded further protection. Together, these studies show that TG2 contributes significantly to overall vascular modulus and vasoreactivity independent of its transamidation function, but that transamidation activity is a significant cause of vascular matrix stiffening during aging. Finally, the Tgm2-C277S mice can be used for in vivo studies to explore the transamidation-independent roles of TG2 in physiology and pathophysiology.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2058-7716Test

الوصول الحر: https://doaj.org/article/e5d70fa9ab5a4776b88454e4bd9e5c23Test

المؤلفون: Huilei Wang, Alan Poe, Lydia Pak, Kavitha Nandakumar, Sandeep Jandu, Jochen Steppan, Reik Löser, Lakshmi Santhanam

المصدر: Communications Biology, Vol 4, Iss 1, Pp 1-10 (2021)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: To address the limitation of inability to detect lysyl oxidase enzymes (LOX) catalytic function associated with diverse disease processes, Wang et al. developed an in situ activity assay by utilizing the reactivity of hydrazides with imines and carbonyls. This assay detects the total LOX activity in situ for both overexpressed and endogenous LOXs in cells and tissue samples.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2399-3642Test

الوصول الحر: https://doaj.org/article/226aeaa38a774c2ebbf2d0e380dfffceTest

المؤلفون: Jochen Steppan, Daniel Nyhan, Lakshmi Santhanam

المصدر: Frontiers in Physiology, Vol 13 (2022)

مصطلحات موضوعية: vasculature, remodeling, stiffness, aging, cardiac, hypertension, Physiology, QP1-981

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fphys.2022.867185/fullTest; https://doaj.org/toc/1664-042XTest

الوصول الحر: https://doaj.org/article/7fcbdc62d3c74310ba7a2ade5ec2a7c1Test