Juanxiu Lv

Prenatal Exposure to Hypoxia Induced Beclin 1 Signaling-Mediated Renal Autophagy and Altered Renal Development in Rat Fetuses

Aims: Hypoxia has adverse effects on renal development. This study was the first to test hypoxia-induced renal autophagy in rat fetuses. Methods: Pregnant rats were exposed to hypoxia or normoxia during pregnancy and fetal kidneys were collected at gestation day 21. Results: Fetal kidney weight and ratio of kidney–body weight were reduced. Histological analysis showed enlargement in Bowman space and wider space between interstitia in the kidneys of fetus exposed to hypoxia. Fetal renal B-cell lymphoma 2 (BCL-2) was decreased accompanied with higher 2′-deoxyuridine 5′-triphosphate nick end-labeling staining and unchanged soluble FAS in the hypoxia group. Hypoxia increased autophagic structures, including autophagosomes and autolysosomes, in fetal kidneys and increased renal APG5L. There was an increase in renal LC3-II, Beclin 1, p-S6, hypoxia inducible factor 1α (HIF-1a), and ratio of LC3-II–LC3-I and a decrease in P62, protein kinase B (AKT), and phosphorylated AKT in the hypoxia group. Both renal mammalian target of rapamycin (mTOR) and Beclin 1 signaling were upregulated. Conclusion: Hypoxia-affected fetal renal development was associated with renal apoptosis and Beclin 1 signaling-mediated autophagy.

Hippocampal apoptosis involved in learning deficits in the offspring exposed to maternal high sucrose diets

The hippocampus plays a crucial role in learning and memory, and neuronal apoptosis in the hippocampus contributes to learning deficits. Metabolism problems in pregnancy related to excessive fuel consumption (e.g., high fat, high sugar) may influence cognitive and behavioral functions in the offspring by affecting developing brain cells. This study determined the influence of maternal high sucrose (HS) diets on behavior and hippocampal neurons in the young offspring. The ratio of brain weight to body weight in the offspring exposed to prenatal HS diets was significantly decreased; the Morris water maze showed that the offspring exposed to prenatal HS diets exhibited increased escape latencies and path length during navigation testing, while there were no changes in time spent in the target quadrant and number of target approaches. In the offspring exposed to prenatal HS, TUNEL-positive cells were significantly increased in CA1, CA2 and CA3 of the hippocampus; protein expression of insulin-like growth factor-I, PI3K and phosphorylated Akt was significantly decreased, while caspase-3 and N-methyl-d-aspartate receptors were significantly increased in the hippocampus, and there was no change in expression of Bcl-2 and Akt. The results demonstrated that prenatal HS diets could induce the spatial acquisition deficits in the young offspring associated with hippocampal apoptosis, and altered signaling factors for antiapoptosis in the hippocampus might play a critical role in cognition disorders in young children.

Herbal drugs against cardiovascular disease: traditional medicine and modern development.

Herbal products have been used as conventional medicines for thousands of years, particularly in Eastern countries. Thousands of clinical and experimental investigations have focused on the effects and mechanisms-of-action of herbal medicine in the treatment of cardiovascular diseases (CVDs). Considering the history of clinical practice and the great potentials of herb medicine and/or its ingredients, a review on this topic would be helpful. This article discusses possible effects of herbal remedies in the prevention and treatment of CVDs. Crucially, we also summarize some underlying pharmacological mechanisms for herb products in cardiovascular regulations, which might provide interesting information for further understanding the effects of herbal medicines, and boost the prospect of new herbal products against CVDs.

Hypoxia‐induced proliferation in mesenchymal stem cells and angiotensin II‐mediated PI3K/AKT pathway

Hypoxia could stimulate proliferation of mesenchymal stem cells (MSCs) under certain conditions. This study determined angiotensin II mechanisms and PI3K/AKT pathway in hypoxia‐induced proliferation of MSCs. Hypoxia (3% oxygen) induced cellular proliferation in mouse MSCs and upregulated endogenous angiotensin II and angiotensin‐converting enzyme in the cell culture and expression of AT1 receptors. The expressions of Sox2, not Oct4 and Rex1, were significantly increased by the hypoxia. The blockade of AT1 receptors, not AT2 receptors, depressed hypoxia induced the proliferative effects. Both hypoxia and exogenous angiotensin II activated p‐AKT. Moreover, AT1 receptor inhibitor blocked the effects of hypoxia‐mediated p‐AKT upregulation. The data demonstrated that the hypoxia at 3% oxygen level could induce mouse MSC proliferation, probably as a result of the activation of PI3K signalling pathways via AT1 receptors. Copyright

Maternal high‐salt diet altered PKC/MLC20 pathway and increased ANG II receptor‐mediated vasoconstriction in adult male rat offspring

SCOPE High-salt diet (HSD) is associated with cardiovascular diseases. This study aims at ascertaining the influence of maternal HSD on offsprings angiotensin II (ANG II)-mediated vasoconstriction and the underlying mechanisms. METHODS AND RESULTS In comparison to a normal-salt diet, HSD used in pregnancy in rats changed the ultrastructures of the coronary artery (CA) in 5-month-old male offspring, and increased ANG II-mediated CA contractility. Measurement of [Ca(2+) ]i in CA using fluorescent fura-2, a Ca(2+) indicator, showed that ANG II-mediated increases in [Ca(2+) ]i were the same between HSD and normal-salt diet groups, but the ratio of diameter change/[Ca(2+) ]i induced by ANG II were significantly higher in HSD groups. Angiotensin II receptor type 1, not angiotensin II receptor type 2, caused ANG II-mediated vasoconstriction. Protein kinase C (PKC) inhibitor GF109203X attenuated the ANG II-mediated vasoconstriction, PKC agonist phorbol12,13-dibutyrate produced a greater contraction. There was an increase in PKCβ mRNA and the corresponding protein abundance in the offspring, whereas other PKC subunits PKCα, PKCδ, and PKCε did not change. Moreover, 20 kDa myosin light chain phosphorylation levels were increased in HSD group. CONCLUSION Maternal HSD affected the developmental programing for the offspring CA, with increased ANG II-mediated vasoconstrictions. The angiotensin II receptor type 1-PKC-20 kDa myosin light chain phosphorylation pathway was the possible mediated cellular mechanism.

Prenatal hypoxia promotes atherosclerosis via vascular inflammation in the offspring rats.

BACKGROUND Hypoxia is a critical contributor to increased risks of cardiovascular diseases, including atherosclerosis, but the detailed mechanism that hypoxia leads to atherosclerosis remains unknown. METHODS Pregnant rats were treated with hypoxia (10.5% oxygen) during pregnancy, and HUVEC cells treated with 1% of oxygen. Blood lipids were tested at fetal stage and adult stage of offspring rats; the level of pro-inflammatory cytokines of HUVEC and offspring rats were investigated, and HIF-1α and NFκB mRNA level were also measured by Q-PCR and Elisa. RESULTS We found that TC, LDL-C, ox-LDL-C, and the receptors of ox-LDL-C (lox-1) of the adult offspring were significantly higher than that of the control, while HDL-C was significantly reduced in hypoxia group. The internal elastic lamina was blocked by smooth muscle cells; and the migration of smooth muscle cells into the intima were observed in hypoxia offspring. Luciferase reporter gene experiment showed that HIF-1α activated NFκB transcription at four discrete binding sites of NFκBp65 promoter, although there was no obvious difference among the four discrete binding sites. Using transfection of pCDNA3.1-HIF-1α on HUVEC cells, HIF-1α significantly activated NFκB transcription at hypoxic conditions (1% O2), and concurrent with increased expression of IL-1β and TNF-α. CONCLUSION Hypoxia during pregnancy activated NFκB transcription to induce pro-inflammatory cytokines, leading to the early stage of atherosclerosis.

Muscarinic-mediated vasoconstriction in human, rat and sheep umbilical cords and related vasoconstriction mechanisms.

The umbilical cord provides nutrition and oxygen to the fetus. The aim of this study was to determine the effects of acetylcholine (ACh) on umbilical cords from humans and other mammals, and the mechanisms of ACh‐mediated vasoconstriction in the human umbilical cord.

Exogenous melatonin reduced blood pressure in late-term ovine fetus via MT1/MT2 receptor pathways.

Melatonin is involved in the regulation of blood pressure through the receptor dependent or independent route. However, the effect of melatonin on fetal blood pressure is unknown. This study investigated the effect of melatonin on blood pressure of the late-term ovine fetus in utero. Melatonin and/or antagonists were intravenously administered into the fetuses. Mean arterial pressure and heart rate were recorded. Fetal blood samples were analyzed for biochemical parameters and hormones, including cortisol, angiotensin I, angiotensin II, aldosterone, atrial natriuretic peptide, corticotrophin-releasing hormone, adrenocorticotropic hormone, and endothelin. Fetal blood pressure was decreased following administration of melatonin, whereas it was increased following administration of luzindole, but not prazosin. Plasma level of endothelin was decreased by melatonin, which was blocked by luzindole. Our study suggested that melatonin reduced fetal blood pressure via MT1/MT2 receptors and possibly involving release of endothelin.

Maternal High-Salt Intake During Pregnancy Reprogrammed Renin–Angiotensin System-Mediated Cardiomyocyte Apoptosis in the Adult Offspring Heart

Aims: Excess salt intake during pregnancy may alter fetal organ structures and functions leading to increased risks in the development of cardiovascular diseases in later life. The present study determined whether and how the prenatal high-salt (HS) diets affect renin–angiotensin system (RAS) that may mediate cardiac cell death. Methods and Results: Angiotensin II receptors, AT1 and AT2, protein expression was increased in the myocardium of the offspring exposed to prenatal HS; apoptotic cells appeared in the myocardium of the adult offspring. Mitochondrion was isolated in cell experiments, and the data showed cardiomyocyte apoptosis requiring cytochrome C release. Pretreating H9C2 cells with AT2 agonist CGP42112A induced cell apoptosis in DNA fragments and activated caspase 3. CGP42112A increased mitochondrion cytochrome C release and apoptosis in the cells. Conclusion: Both in vitro and in vivo study demonstrated that cardiomyocyte apoptosis was related to AT2 activation. Prenatal HS diets may reprogram RAS that mediates apoptosis in the offspring myocardium, and AT2 may contribute to cardiomyocyte apoptosis via the cytochrome C release pathway.

High-salt diets during pregnancy increases renal vascular reactivity due to altered soluble guanylyl cyclase-related pathways in rat offspring

Adverse prenatal factors such as overtake of salt or fat food are potential risks for cardiovascular diseases in offspring. This study tested the hypothesis that prenatal high-salt (HS) diets may influence renal vascular tone and attenuates signaling pathways related to soluble guanylyl cyclase (sGC) or/and large-conductance Ca(2+)-activated K(+) (BKCa) channels in the offspring. Pregnant rats were fed either normal salt (NS) (1% NaCl) or HS (8% NaCl) diet for the whole gestation. Offspring were maintained on NS diets. Renal interlobar arteries in offspring were tested for vascular responses to phenylephrine (Phe), K(+) channels and signal pathways related to sGC. Phe induced higher vessel tension in interlobar arteries of the HS offspring. Following pretreatment with BKCa channel inhibitor iberiotoxin, Phe-mediated vasoconstrictions were decreased in HS offspring compared to NS. Phe-mediated constrictions following pretreatment with NO synthase inhibitor N(G)-nitro-l-arginine methyl ester or sGC inhibitor 1H-1,2,4-oxadiazolo-4,3-quinoxalin-1-one in the HS offspring were less sensitive than NS. The whole-cell K(+) currents and the component of BKCa channels were not changed in smooth muscle cells from interlobar arteries, whereas the K(+) currents stimulated by sGC activator BAY41-2272 were reduced in the HS offspring. The protein expressions of sGC β1 and β2 in the interlobar arteries of HS offspring were reduced. The results showed that chronic overintake of salt during pregnancy could increase renal vascular tone in the offspring. The affected signal pathways included down-regulation of sGC function and expression.