Try a new search

Format these results:

Searched for:

person:schmia1000 or ramasr02 or woodsl05 or arival01 or Borodj02 or sc5616 or jd1904 or Detrec02 or ld1914 or gujraa01 or juranj01 or lopezr09 or mm8848 or mangak02 or manigm02 or quadrn01 or ruizh03 or lms587 or spelim01 or szostn01 or Yepurg01 or zhangj10

active:yes

exclude-minors:true

Total Results:

419


The cardioprotective role of sirtuins is mediated in part by regulating KATP channel surface expression

Tuncay, Erkan; Gando, Ivan; Huo, Jian-Yi; Yepuri, Gautham; Sampler, Natalie; Turan, Belma; Yang, Hua-Qian; Ramasamy, Ravichandran; Coetzee, William A
Sirtuins are NAD+-dependent deacetylases with beneficial roles in conditions relevant to human health, including metabolic disease, type II diabetes, obesity, cancer, aging, neurodegenerative diseases, and cardiac ischemia. Since ATP-sensitive K+ (KATP) channels have cardioprotective roles, we investigated whether they are regulated by sirtuins. Nicotinamide mononucleotide (NMN) was used to increase cytosolic NAD+ levels and to activate sirtuins in cell lines, isolated rat and mouse cardiomyocytes or insulin-secreting INS-1 cells. KATP channels were studied with patch clamping, biochemistry techniques, and antibody uptake experiments. NMN led to an increase in intracellular NAD+ levels and an increase in the KATP channel current, without significant changes in the unitary current amplitude or open probability. An increased surface expression was confirmed using surface biotinylation approaches. The rate of KATP channel internalization was diminished by NMN, which may be a partial explanation for the increased surface expression. We show that NMN acts via sirtuins since the increased KATP channel surface expression was prevented by blockers of SIRT1 and SIRT2 (Ex527 and AGK2) and mimicked by SIRT1 activation (SRT1720). The pathophysiological relevance of this finding was studied using a cardioprotection assay with isolated ventricular myocytes, in which NMN protected against simulated ischemia or hypoxia in a KATP channel-dependent manner. Overall, our data draw a link between intracellular NAD+, sirtuin activation, KATP channel surface expression, and cardiac protection against ischemic damage.
PMCID:10110703
PMID: 36878847
ISSN: 1522-1563
CID: 5462392

Recipients of the 2023 Early Career Investigator Awards

Schmidt, Ann Marie
PMID: 36891901
ISSN: 1524-4636
CID: 5464752

Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation

Gopal, Keshav; Karwi, Qutuba G; Tabatabaei Dakhili, Seyed Amirhossein; Wagg, Cory S; Zhang, Liyan; Sun, Qiuyu; Saed, Christina T; Panidarapu, Sai; Perfetti, Riccardo; Ramasamy, Ravichandran; Ussher, John R; Lopaschuk, Gary D
BACKGROUND:Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism. METHODS:Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism. RESULTS: in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy. CONCLUSIONS:Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.
PMCID:10053619
PMID: 36978133
ISSN: 1475-2840
CID: 5463212

DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice

Senatus, Laura; Egaña-Gorroño, Lander; López-Díez, Raquel; Bergaya, Sonia; Aranda, Juan Francisco; Amengual, Jaume; Arivazhagan, Lakshmi; Manigrasso, Michaele B; Yepuri, Gautham; Nimma, Ramesh; Mangar, Kaamashri N; Bernadin, Rollanda; Zhou, Boyan; Gugger, Paul F; Li, Huilin; Friedman, Richard A; Theise, Neil D; Shekhtman, Alexander; Fisher, Edward A; Ramasamy, Ravichandran; Schmidt, Ann Marie
Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr-/- mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr-/- mice, male Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis compared to Ldlr-/- mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1.
PMCID:10023694
PMID: 36932214
ISSN: 2399-3642
CID: 5449062

Obesity and Overweight: Probing Causes, Consequences, and Novel Therapeutic Approaches Through the American Heart Association's Strategically Focused Research Network

Clark, Jeanne M; Garvey, W Timothy; Niswender, Kevin D; Schmidt, Ann Marie; Ahima, Rexford S; Aleman, Jose O; Battarbee, Ashley N; Beckman, Joshua; Bennett, Wendy L; Brown, Nancy J; Chandler-Laney, Paula; Cox, Nancy; Goldberg, Ira J; Habegger, Kirk M; Harper, Lorie M; Hasty, Alyssa H; Hidalgo, Bertha A; Kim, Sangwon F; Locher, Julie L; Luther, James M; Maruthur, Nisa M; Miller, Edgar R; Sevick, Mary Ann; Wells, Quinn
As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN-designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity-focused investigators and next-step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.
PMID: 36752232
ISSN: 2047-9980
CID: 5420832

The receptor for advanced glycation end products and its ligands' expression in OVE26 diabetic sciatic nerve during the development of length-dependent neuropathy

Zglejc-Waszak, Kamila; Schmidt, Ann Marie; Juranek, Judyta K
Type 1 diabetes (T1D) may affect the peripheral nervous system and alter the expression of proteins contributing to inflammation and cellular cytoskeleton dysfunction, in most cases leading to the development of diabetic length-dependent neuropathy (DLDN). In the present study, we performed immunohistochemistry (IHC) to probe the expression of the receptor for advanced glycation end products (RAGE); its key ligands, high-mobility group box 1 (HMGB1), S100 calcium-binding protein B (S100B), and carboxymethyl-lysine (CML - advanced glycation end products (AGE)); and its cytoplasmic tail-binding partner, diaphanous related formin 1 (DIAPH1) and associated molecules, beta-actin (ACTB) and profilin 1 (PFN1) proteins in sciatic nerves harvested from seven-month old FVB/OVE26 mice with genetically-mediated T1D. We found that the amount of RAGE, HMGB1, and S100B proteins was elevated in diabetic vs the non-diabetic groups, while the amount of DIAPH1, ACTB, as well as PFN1 proteins did not differ between these groups. Moreover, our data revealed linear dependence between RAGE and HMGB1 proteins. Interaction criss-cross of selected sets of proteins in the sciatic nerve revealed that there were connected in a singular network. Our results indicate that T1D may alter expression patterns of RAGE axis proteins and thus contribute to DLDN.
PMID: 35915909
ISSN: 1440-1789
CID: 5287902

RAGE/DIAPH1 and atherosclerosis through an evolving lens: Viewing the cell from the "Inside "“ Out"

Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie
Background and aims: In hyperglycemia, inflammation, oxidative stress and aging, Damage Associated Molecular Patterns (DAMPs) accumulate in conditions such as atherosclerosis. Binding of DAMPs to receptors such as the receptor for advanced glycation end products (RAGE) activates signal transduction cascades that contribute to cellular stress. The cytoplasmic domain (tail) of RAGE (ctRAGE) binds to the formin Diaphanous1 (DIAPH1), which is important for RAGE signaling. This Review will detail the evidence linking the RAGE/DIAPH1 signaling pathway to atherosclerosis and envisages future therapeutic opportunities from the "inside-out" point of view in affected cells. Methods: PubMed was searched using a variety of search terms, including "receptor for advanced glycation end products" along with various combinations including "and atherosclerosis," "soluble RAGE and atherosclerosis," "statins and RAGE," "PPAR and RAGE" and "SGLT2 inhibitor and RAGE." Results: In non-diabetic and diabetic mice, antagonism or global deletion of Ager (the gene encoding RAGE) retards progression and accelerates regression of atherosclerosis. Global deletion of Diaph1 in mice devoid of the low density lipoprotein receptor (Ldlr) significantly attenuates atherosclerosis; mice devoid of both Diaph1 and Ldlr display significantly lower plasma and liver concentrations of cholesterol and triglyceride compared to mice devoid of Ldlr. Associations between RAGE pathway and human atherosclerosis have been identified based on relationships between plasma/serum concentrations of RAGE ligands, soluble RAGEs and atherosclerosis. Conclusions: Efforts to target RAGE/DIAPH1 signaling through a small molecule antagonist therapeutic strategy hold promise to quell accelerated atherosclerosis in diabetes and in other forms of cardiovascular disease.
SCOPUS:85175205737
ISSN: 0021-9150
CID: 5616642

Messenger RNA in lipid nanoparticles rescues HEK 293 cells from lipid-induced mitochondrial dysfunction as studied by real time pulse chase NMR, RTPC-NMR, spectroscopy

Sciolino, Nicholas; Reverdatto, Sergey; Premo, Aaron; Breindel, Leonard; Yu, Jianchao; Theophall, Gregory; Burz, David S; Liu, Anna; Sulchek, Todd; Schmidt, Ann Marie; Ramasamy, Ravichandran; Shekhtman, Alexander
Analytical tools to study cell physiology are critical for optimizing drug-host interactions. Real time pulse chase NMR spectroscopy, RTPC-NMR, was introduced to monitor the kinetics of metabolite production in HEK 293T cells treated with COVID-19 vaccine-like lipid nanoparticles, LNPs, with and without mRNA. Kinetic flux parameters were resolved for the incorporation of isotopic label into metabolites and clearance of labeled metabolites from the cells. Changes in the characteristic times for alanine production implicated mitochondrial dysfunction as a consequence of treating the cells with lipid nanoparticles, LNPs. Mitochondrial dysfunction was largely abated by inclusion of mRNA in the LNPs, the presence of which increased the size and uniformity of the LNPs. The methodology is applicable to all cultured cells.
PMCID:9789524
PMID: 36566335
ISSN: 2045-2322
CID: 5468062

Association between depression, happiness, and sleep duration: data from the UAE healthy future pilot study

Al Balushi, Mitha; Al Balushi, Sara; Javaid, Syed; Leinberger-Jabari, Andrea; Al-Maskari, Fatma; Al-Houqani, Mohammed; Al Dhaheri, Ayesha; Al Nuaimi, Abdullah; Al Junaibi, Abdullah; Oumeziane, Naima; Kazim, Marina; Al Hamiz, Aisha; Haji, Muna; Al Hosani, Ayesha; Abdel Wareth, Leila; AlMahmeed, Wael; Alsafar, Habiba; AlAnouti, Fatme; Al Zaabi, Eiman; K Inman, Claire; Shahawy, Omar El; Weitzman, Michael; Schmidt, Ann Marie; Sherman, Scott; Abdulle, Abdishakur; Ahmad, Amar; Ali, Raghib
BACKGROUND:The United Arab Emirates Healthy Future Study (UAEHFS) is one of the first large prospective cohort studies and one of the few studies in the region which examines causes and risk factors for chronic diseases among the nationals of the United Arab Emirates (UAE). The aim of this study is to investigate the eight-item Patient Health Questionnaire (PHQ-8) as a screening instrument for depression among the UAEHFS pilot participants. METHODS:The UAEHFS pilot data were analyzed to examine the relationship between the PHQ-8 and possible confounding factors, such as self-reported happiness, and self-reported sleep duration (hours) after adjusting for age, body mass index (BMI), and gender. RESULTS:Out of 517 participants who met the inclusion criteria, 487 (94.2%) participants filled out the questionnaire and were included in the statistical analysis using 100 multiple imputations. 231 (44.7%) were included in the primary statistical analysis after omitting the missing values. Participants' median age was 32.0 years (Interquartile Range: 24.0, 39.0). In total, 22 (9.5%) of the participant reported depression. Females have shown significantly higher odds of reporting depression than males with an odds ratio = 3.2 (95% CI:1.17, 8.88), and there were approximately 5-fold higher odds of reporting depression for unhappy than for happy individuals. For one interquartile-range increase in age and BMI, the odds ratio of reporting depression was 0.34 (95% CI: 0.1, 1.0) and 1.8 (95% CI: 0.97, 3.32) respectively. CONCLUSION/CONCLUSIONS:Females are more likely to report depression compared to males. Increasing age may decrease the risk of reporting depression. Unhappy individuals have approximately 5-fold higher odds of reporting depression compared to happy individuals. A higher BMI was associated with a higher risk of reporting depression. In a sensitivity analysis, individuals who reported less than 6 h of sleep per 24 h were more likely to report depression than those who reported 7 h of sleep.
PMCID:9587590
PMID: 36271400
ISSN: 2050-7283
CID: 5352582

"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency"

Oluwadare, Jide; Cabodevilla, Ainara G; Son, Ni-Huiping; Hu, Yunying; Mullick, Adam E; Verano, Michael; Alemán, Jose O; Ramasamy, Ravichandran; Goldberg, Ira J
Lipid accumulation in non-adipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human Neutral Lipid Storage Disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl knockout mice a low- or high-fat diet, we found heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double knockout mice also deficient in either cardiac lipoprotein lipase (LpL) or cluster of differentiation (CD) 36, which is involved in an LpL-independent pathway for fatty acid uptake in the heart. We show neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo fatty acid synthesis. Thus, we conclude pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.
PMID: 36115595
ISSN: 1539-7262
CID: 5336622