bluuebunny/crossref_metadata_2025_split huggingface dataset:
EET‐dependent attenuation of coronary myogenic constriction in response to deletion/downregulation of soluble epoxide hydrolase
Authors: Froogh Ghezal , Qin Jun , Kandhi Sharath , Jiang Houli , Sun Dong , Huang An 
Published: November 2023

Soluble epoxide hydrolase (sEH) catabolizes epoxyeicosatrienoic acids (EETs) to form DHETs that lack, or have less, cardioprotective properties. Thus, we hypothesized that a sex‐different regulation of pressure‐induced myogenic constriction in coronary arteries involves sEH‐dependent signaling. Pressure‐diameter relationships were assessed in isolated and cannulated coronary arteries of male (M) and female (F) wild type (WT) and sEH‐knockout (KO) mice. All vessels constricted in response to increases in intraluminal pressure from 60 to 120 mmHg. Myogenic constriction was significantly attenuated, associated with higher cardiac EETs and lower DHETs in M‐KO, F‐WT and F‐KO mice compared to M‐WT controls. Blockade of EETs with 14,15‐EEZE prevented the attenuated myogenic constriction in sEH‐KO mice. In the presence of EEZE, pressure‐diameter curves of females presented an upward‐shift from those of males, manifesting a sex‐different phenotype. Additional administration of L‐NAME eliminated the sex‐difference, leading to four overlapped pressure‐diameter curves. Cardiac sEH was downregulated in F‐WT compared to M‐WT mice, whereas the expression of eNOS was comparable among the groups. In summary, in combination with NO, the increased EET bioavailability as a function of genetic deletion and/or downregulation of sEH accounts for the female‐favorable attenuation of pressure‐induced constriction.Support or Funding InformationThis work was supported by grant NIH HL070653 and HL34300
Comparison in young White European (WE) and South Asian (SA) men of endothelium‐dependent cutaneous vasodilator responses: contribution of cyclooxygenase (COX) products
Authors: Tsitoglou Kyriakos , Martin Una , Marshall Janice 
Published: November 2023

It is established that cardiovascular disease is more prevalent in South Asians (SA) than White Europeans (WE). The prevalence of diabetes central obesity and metabolic syndrome is particularly high in SAs, disorders that are associated with endothelial dysfunction. It is not known whether early markers of endothelial dysfunction can be detected even in young healthy SAs. Thus, we have compared responses evoked in recreationally‐active WE and SA men (18–25 years; n=10 in each case). SAs were 1st or 2nd generation residents in the UK with mother and father originating from India, Sri Lanka, Bangladesh or Pakistan; WEs were UK residents with WE parents. By using laser Doppler fluximetry, we monitored changes in cutaneous red cell flux (RCF) evoked in the cutaneous circulation of the forearm by iontophoresis of the endothelium‐dependent dilator acetylcholine (ACh, 8 × 20s pulses: 7 at 100 μA, 8th at 200 μA, at 60s intervals) and by release of arterial occlusion for 3 min (reactive hyperaemia). Responses were tested before and after aspirin (600mg p.o.) to assess the role of COX products. Mean arterial blood pressure (ABP) was continuously monitored by photoplethysmography using a finger cuff. Resting ABP was similar in WEs and SAs (124±1.8/70±1.7 vs 116.6±2.0/65.4±1.6 mmHg) and did not change during the protocol. Baseline RCF was also similar in WEs and SAs: 19.7±1.9 vs 12.3±0.9 perfusion units (PU), respectively. Further, ACh evoked similar dilator responses in WEs and SA, maximum RCF reaching 192.2±5.5 and 182.83 ± 5.20 perfusion units (PU) respectively. Aspirin had no net effect on ACh‐induced dilatation in either group (WEs: 182.6±4.5 and SAs: 193.0± 7.7 PU) indicating any influence of COX dilator and vasoconstrictor products was balanced in both WEs and SAs. By contrast, before aspirin, reactive hyperaemia was substantially larger in WEs than SA, peak RCF being 92.9±2.5 vs 74.2±3.1*PU, *: P<0.01 RMANOVA). Further, aspirin attenuated reactive hyperaemia in WEs, peak RCF being only 75.1 ± 2.6§PU: §: P<0.001 vs control response, but enhanced reactive hyperaemia in SAs, peak RCF reaching 84.7±2.7§PU. These results suggest that in young SA men, who have no overt signs of cardiovascular disease and are normotensive, there are already signs of endothelial dysfunction. Agonist‐evoked endothelium‐dependent dilatation is apparently normal in SAs with no net contribution from COX dilator or vasoconstrictor products, suggesting that nitric oxide and/or Endothelium‐dependent hyperpolarising factor are the main contributors in both ethnicities. However, reactive hyperaemia, which is induced by the combination of shear‐stress and metabolic stimuli, is blunted in young SAs relative to WEs and this is attributable to a predominating influence of vasoconstrictor COX products in SAs, but vasodilator COX products in WEs.Support or Funding InformationAlexander S. Onassis Public Benefit Foundation
Chronic Nicotine Exposure Exacerbates Transient Focal Cerebral Ischemia‐Induced Brain Injury
Authors: Li Chun , Sun Hong , Arrick Denise M , Mayhan William G 
Published: November 2023

Tobacco smoking is a risk factor contributing to the development and progression of ischemic stroke. Among many chemicals in tobacco, nicotine may be a key contributor. We hypothesized that nicotine alters the balance between oxidant and antioxidant networks leading to an increase in brain injury following transient focal cerebral ischemia. Male Sprague‐Dawley were treated with nicotine (2 or 4 mg/kg/day) for 4 weeks via an implanted subcutaneous osmotic minipump and subjected to a 2‐hour middle cerebral artery occlusion (MCAO). Infarct size and neurological deficits were evaluated at 24 hours of reperfusion. Superoxide levels were determined by lucigenin‐enhanced chemiluminescence. Expression of oxidant and antioxidant proteins was measured using Western Blot analysis. We found that chronic nicotine exposure significantly increased infarct size and worsened neurological deficits. In addition, nicotine significantly elevated superoxide levels of cerebral cortex under basal conditions. Cerebral ischemia/reperfusion (I/R) produced an increase in superoxide levels of cerebral cortex in control group, but no further increase was found in the nicotine group. Furthermore, chronic nicotine exposure did not alter protein expression of NADPH oxidase, but significantly decreased uncoupling protein‐2 (UCP‐2) in the cerebral cortex, MnSOD in the cerebral cortex and cerebral arteries. Our findings suggest that nicotine‐induced exacerbation in brain damage following transient focal cerebral ischemia may be related to a pre‐existing oxidative stress via decreasing of UCP‐2 and MnSOD.Support or Funding InformationFunded by a fellowship from Center for Cardiovascular Diseases and Sciences, LSU Health Sciences Center‐Shreveport
Cross Tolerance and Potentiation of Toll‐like Receptors in Endothelial Cells
Authors: Stark Ryan J , Koch Stephen R , Lamb Fred S , Sherwood Edward R 
Published: November 2023

Toll‐like receptors (TLR) are important regulators of inflammation in endothelial cells. Activation of TLRs can reduce the pro‐inflammatory response to a subsequent TLR challenge, inducing a state of “tolerance”. We hypothesized that activation of TLR2 and TLR3 would induce cross tolerance to TLR4 activation. We cultured human microvascular (HMVECs) and umbilical vein (HUVECs) endothelial cells and exposed them to the TLR4 agonist lipopolysaccharide (LPS), the TLR3 agonist poly I:C, or the TLR1/2 agonist Pam3CSK4 for 16 hours. Cells were washed and then allowed to rest in media for 30 hours. Afterwards, cells were re‐exposed to different TLR ligands for 16 hours. Inflammation was assessed by quantifying IL‐6 levels in the culture media. Initial LPS exposure rendered both HUVECs and HMVECs tolerant to subsequent LPS exposure with a 47% and 48% reduction in IL‐6, respectively (p <0.05). Contrary to this, initial exposure to poly I:C increased IL‐6 production after LPS re‐exposure compared to LPS alone by 25% in HMVECs and 35% in HUVECs (p <0.05). Interestingly, though Pam3CSK4 produced little IL‐6 in HMVECs compared HUVECs (11.18 pg/ml HMVECs vs. 2197 pg/ml in HUVECs), initial exposure of HMVECs to Pam3CSK4 reduced IL‐6 in cells re‐exposed to LPS by 43% compared to LPS alone(p <0.05). These studies provide new knowledge into the modulatory relationship between TLRs in inciting inflammation in endothelial cells.Support or Funding InformationThis work was supported by the National Institute of General Medical Sciences (K08‐GM117367, R.S., R01‐GM104306, E. S.)
Overweight was related with sympathetic activation in offspring of hypertensives
Authors: Viana Ariane Oliveira , Rosa Fernando Alves Santa , Nascimento Mario Cesar , Shimojo Guilherme Lemos , De Paiva Júlia , De Angelis Kátia 
Published: November 2023

Hypertension is a clinical condition with high rates of cardiac events and mortality. This disease has been related to overweight/obesity, cardiovascular and autonomic dysfunctions. The objective of this study was to evaluate anthropometric, hemodynamic and autonomic parameters in sedentary men with a positive (HS n= 32) or negative (NS n= 30) familial history of hypertension. A cross‐sectional study was performed with 62 healthy sedentary men (20–48 years old). The body mass index (BMI) was calculated and the blood pressure (BP) was measured 3 times by the auscultatory method. The RR interval was recording during a 20 minute period at rest using a frequencimeter (Polar® RS800 model). The heart rate variability was evaluated in the time and frequency domain. The overweight subjects (n=45, BMI: 29.22 [IQ 26.96–30.87Kg/m2]) presented significantly higher systolic BP (116.66 [IQ 88–128mmHg] vs. 104 [IQ 76.33–118.33mmHg]) and diastolic BP (85.33 [IQ 80.83–93.94mmHg] vs. 82.88 [IQ 73.00–86.22mmHg]) as compared to the eutrophic group (n= 17, BMI: 24.30 [IQ 24.78–29.72Kg/m2]). In addition, positive correlations were observed between the sympathovagal balance with the systolic BP (r = 0.377, p = 0.011) and the mean BP (r = 0.406, p = 0.006). The BMI was also correlated with diastolic BP (r = 0.335, p = 0.025). Regarding the familial history of hypertension, we observed increased BP and sympathetic modulation in the HS group compared to the NS group. Moreover, BP was increased in overweight HS subjects as compared to overweight NS. Correlation analysis involving HS and NS groups, showed positive correlations between sympathovagal balance with mean BP (r = 0.257, p = 0.044) and systolic BP (r = 0.262, p = 0.039); BMI with diastolic BP (r = 0.389, p = 0.002) and systolic BP (r = 0.336, p = 0.008). In conclusion, the overweight was related with sympathetic activation and BP increase in general populations as well as in offspring of hypertensives.Support or Funding InformationCnpq, Capes, UNINOVE
Chronic Vagus Nerve Stimulation Attenuates Renal Inflammation in Autoimmune‐Induced Hypertension
Authors: Pham Grace S , Fairley Amber S , Maloy Charles I , Mathis Keisa W 
Published: November 2023

Chronic renal inflammation has been implicated in the pathogenesis of hypertension, which identifies the autoimmune disease systemic lupus erythematosus (SLE) as a compelling disease model due to its key features of lupus nephritis and prevalent hypertension. The cholinergic anti‐inflammatory pathway is an endogenous, vagally‐mediated neuroimmune pathway that, when impaired, may influence the development of chronic inflammation. While stimulation of the cholinergic anti‐inflammatory pathway attenuates inflammation in models of sepsis and other inflammatory diseases, it is not clear if the pathway is impaired in SLE, nor whether its stimulation is protective in SLE. We hypothesized that pharmacological activation of the cholinergic anti‐inflammatory pathway at the level of the vagus nerve would decrease renal inflammation and therefore blood pressure in a murine model of SLE hypertension. Initially, female SLE (NZWF1) and control (NZW) mice were administered the efferent vagal stimulant, CNI‐1493 (Semapimod hydrochloride; 8 mg/kg IP) or saline twice per week for 4 weeks starting at 30 weeks of age. SLE mice had 1143±439% (p<0.001), 74±24% (p=0.006), and 225±124% (p=0.009) higher renal cortical expression of the inflammatory mediators TNF‐α, IL‐1, and high mobility group box (HMGB)‐1 than controls (n=3–5/group). CNI‐1493 reduced TNF‐α, IL‐1 and HMGB‐1 by 13±11% (p=NS), 29±11% (p=0.05), and 42±5% (p=NS) in SLE mice. We continued to test our hypothesis by stimulating the efferent vagus via administration of the centrally‐acting acetylcholinesterase inhibitor, galantamine (GAL; 4mg/kg IP), or saline to SLE and control mice for 14 consecutive days starting at 32 weeks of age. SLE mice had 502±332% (p=0.037) and 345±35% (p=0.002) higher renal cortical expression of TNF‐α and IL‐6 than controls (n=2–4/group). GAL lowered TNF‐α and IL‐6 by 56 ±16% (p=NS) and 61±2% (p=0.006) in SLE mice. Interestingly, when we assessed whether mean arterial pressure (MAP) was altered following vagal stimulation and subsequent reduction of renal cytokines, we found that MAP (n=3–6/group) was higher in SLE mice compared to controls (143±11 vs. 116±4; p=0.003) and that both CNI‐1493 and GAL prevented the rise in MAP in SLE mice (130±4 and 135±7, respectively). These preliminary results suggest that chronic vagal nerve stimulation attenuates renal inflammation and therefore prevents the development of hypertension in SLE. Ultimately, delineating the role of the cholinergic anti‐inflammatory pathway in SLE could support further investigation into the pathway's role in other autoimmune diseases, as well as essential hypertension, which has recently been shown to arise from an inflammatory etiology.Support or Funding InformationStudies supported by the AHA (#14SDG18320033) and UNTHSC (Faculty Pilot Grant)
Does chronic inhibition of brain endoplasmic reticulum (ER) stress alter metabolic and cardiovascular function in obese melanocortin‐4 deficient rat?
Authors: do Carmo Jussara M. , da Silva Alexandre A. , Yoo Jung , Moak Sydney P. , Spradley Frank , Hall John E. 
Published: November 2023

The central nervous system (CNS) melanocortin system plays a key role in regulating metabolic function and in mediating obesity‐induced hypertension. Although, endoplasmic reticulum (ER) stress has been suggested to alter hypothalamic pathways that regulate food intake, body weight and blood pressure (BP), its role in mediating cardiovascular and metabolic dysfunction in obesity is still unclear. In this study we examined the role of brain ER stress in controlling blood pressure (BP) and metabolic functions in obese melanocortin‐4 receptor (MC4R) deficient rats. MC4R knockout (MC4R−/−, n=5) and control wild‐type Wistar Hannover rats (WT, n=5) were implanted with blood pressure (BP) telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the third ventricle at 22 weeks of age. After 10 days of recovery, food intake, BP and HR were measured 24‐hrs/day. After stable baseline measurements for 4 days, tauroursodeoxycholic acid (TUDCA, 7mg/hr, ICV) was infused via osmotic minipump for 7 consecutive days to inhibit brain ER stress. At baseline, MC4R−/− rats ate 42% more food and were 41% heavier than WT rats. MAP was higher (118±1 vs. 111±1 mmHg) and HR was lower (332±3 vs. 353±4 bpm) in MC4R−/− rats. Inhibition of brain ER stress significantly decreased cumulative net food intake (−26+4 vs. −16+5 g) while causing no changes in blood glucose levels (WT: 97±2 vs. 95±4 and MC4R−/−: 109±4 vs.106± 6 mg/dl) or body weight (WT: 446±11 vs. 448±12 and MC4R−/−: 629±23 vs.631± 30 g). Inhibition of brain ER stress also did not alter BP in either group (3 and 2 mmHg) but increased HR (8±2 and 19±4 bpm), respectively, in WT and MC4R−/− rats. These results suggest that chronic inhibition of brain ER stress reduced appetite but did not alter body weight, blood glucose or BP in WT or MC4R−/− rats.Support or Funding Information(NHLBI‐PO1HL51971, NIGMS‐P20GM104357 and AHA SDG5680016)
Sex Differences in Renal Sodium Transporter Gene Expression
Authors: Patel Ravi S. , Solocinski Kristen , Cheng Kit‐Yan , Gumz Michelle L. 
Published: November 2023

Regulation of sodium balance and blood volume by the kidneys is an important determinant of blood pressure control. Although the causative mechanisms remain unclear, it is well established that male sex is associated with higher blood pressure and increased cardiovascular risk compared to female sex. In order to determine a possible role for renal sodium transporters in sex‐dependent blood pressure regulation, we examined a number of renal transport genes in the kidney cortex of male and female mice. Under normal conditions, the circadian clock protein Per1 is a positive regulator of sodium transport genes including αENaC (α subunit of the epithelial sodium channel), Wnk1(with‐no‐lysine kinase 1), and NCC (sodium‐chloride cotransporter). Using qPCR and western blot analysis, we found significant differences between the sexes in a number of renal sodium transport genes and clock genes. Interestingly, Per1 (Period 1), Sgk1 (serum and glucocorticoid kinase 1), αENaC, Edn‐1 (Endothelin‐1), and NCC expression was higher in females compared to males whereas Wnk1 expression was equivalent between the sexes. These data show significant sex‐dependent differences in gene expression of distinct sodium transport genes and circadian clock genes. Whether or not these differences are related to sex‐dependent differences in blood pressure remains to be determined.Support or Funding InformationThis work was supported by NIH DK085193 and DK098460, the ASN Foundation for Kidney Research to MLG and 2T32HL083810 to KS.
Cyclic‐AMP Regulates Glycogen Synthase Kinase‐3β by a Feed‐Forward Mechanism in Polycystic Kidney Disease
Authors: Kakade Vijayakumar R , Tao Shixin , Zhou Xia , Li Xiaogang , Pandey Pankaj , Rajagopal Madhumita , Rao Reena 
Published: November 2023

Glycogen synthase kinase 3β (GSK3β) is a serine/threonine protein kinase that plays an important role in cell survival, proliferation, metabolism and differentiation. GSK3β is known to be regulated at the level of its activity. However, GSK3β expression is increased in diabetes, Alzheimer's disease and certain cancers, although the mechanism is not clear. We observed increased GSK3β expression in polycystic kidney disease (PKD), a disease characterized by progressive cyst expansion that leads to end stage renal disease. Since GSK3β plays a pathophysiological role in disease progression in PKD, the current studies examined the mechanism for the increased GSK3β expression and its significance in PKD. In mouse models of autosomal dominant and autosomal recessive PKD, increase in renal GSK3β expression corresponded with increase in renal cAMP levels and disease progression. Examination of the GSK3β promoter revealed five cAMP response elements (CREs), potential binding sites for the transcription factor, CRE‐binding protein (CREB). Studies using M1‐cortical collecting duct, PKD1‐ gene knockout (PKD1‐‐KO) and control cells demonstrated that GSK3β is a cAMP responsive gene and elevated cAMP levels, as seen in PKD, can increase GSK3β protein and mRNA levels. CREB was found to bind to the GSK3β promoter and to be essential for cAMP mediated regulation of GSK3β expression. Importantly, this regulation was demonstrated to be part of a feed‐forward loop in which cAMP through CREB regulates GSK3β expression, and GSK3β in turn regulate cAMP levels and CREB activity. Inhibition of CREB reduced forskolin induced cAMP generation, which could be rescued by overexpression of constitutively active GSK3β showing that the relation between cAMP, CREB and GSK3β is cyclic in nature. Moreover, inhibition of GSK3β, or CREB significantly reduced cyst expansion as well as trans‐epithelial fluid secretion in vitro. Thus, GSK3β is regulated by a cAMP and CREB dependent feed forward loop, and disruption at any point of this cycle may be therapeutically useful to reduce cyst expansion and preserve renal function in PKD.Support or Funding InformationNIDDK Support
The α2‐Subunit of AMP‐activated Protein Kinase Is a Potent Modulator of Myocardial Diastolic Calcium Homeostasis
Authors: Pohl Ulrich , Fein Evelyn , Kameritsch Petra , Schneider Holger , Engelhardt Stefan , Dendorfer Andreas , Blodow Stephanie 
Published: November 2023

RationaleThe heterotrimeric enzyme 5′‐adenosine monophosphate‐activated protein kinase (AMPK) is known to have cardioprotective effects which may be partly due to a participation in the control of intracellular calcium concentration. Recently, we described in vascular smooth muscle a dilator role for AMPK which is due to sarcoplasmic reticulum Ca2+‐ATPase (SERCA)‐dependent calcium decrease. The present study elucidates a possible role of AMPK for myocardial diastolic calcium decrease.ObjectiveTo investigate, whether AMPK contributes to the regulation of SERCA dependent myocardial diastolic calcium homeostasis via phosphorylation of phospholamban (PLN) and to identify which catalytic subunit of AMPK was involved.Methods and ResultsFreshly obtained heart slices of wildtype and AMPKα2‐gene‐deficient mice were analyzed by recording contraction amplitudes and relaxation velocities in the presence or absence of the AMPK activator A769662. A769662 (30 μM, 15 min) increased phosphorylation of AMPKThr172 showing effective activation of the enzyme. The AMPK stimulator induced positive inotropic (contraction amplitudes +75%) and lusitropic (relaxation velocity +71%) effects in isolated heart slices (p<0.05 vs controls, n=6–11). The latter corresponded to a significant shortening of the time constant of Ca2+‐transient decay (tau, −25%, Fura2 method, n=15–23) which was similar to the effect observed after stimulation with isoproterenol (100 nM). A second structurally different AMPK activator, PT1 (30 μM), virtually mimicked the A769662‐induced positive inotropy and lusitropy. Western Blots (n=3–9) of freshly isolated, A769662‐stimulated adult mouse cardiomyocytes showed an enhanced phosphorylation of PLN, but exclusively at the regulatory site Thr17, whereas isoproterenol led to increases in phosphorylation of both regulatory sites, PLNSer16 and Thr17. The A769662‐induced effects were blunted in slices and cells isolated from AMPKα2‐gene‐deficient mice while isoproterenol was still effective (n=4–5).ConclusionsOur data suggest that AMPK, via its catalytic α2‐subunit, induces phosphorylation of PLNThr17 thereby accelerating diastolic Ca2+‐decrease and increasing relaxation velocity. This novel AMPK‐PLN‐ pathway could serve as a valuable new therapeutic target in failing hearts showing reduced responsiveness to b‐adrenergic stimulation.Support or Funding InformationSupported by the DZHK (German Centre for Cardiovascular Research)