Renalase, a novel amine oxidase, is secreted by kidney. It regulates heart function and blood pressure by degrading catecholamines. Hormones secreted by the kidney are associated with cardiovascular disease. Renalase, as a new biomarker of heart and kidney functional correlation, can lower blood pressure, protect ischemic heart muscle, improve heart function and degrade catecholamine.
Animals ; Cardiovascular Diseases ; physiopathology ; Heart Failure ; physiopathology ; Humans ; Hypertension ; physiopathology ; Monoamine Oxidase ; genetics ; physiology ; Myocardial Ischemia ; physiopathology

OBJECTIVETo investigate the mechanisms by which hypertension occurs in D(3) dopamine receptor null mice (D(3)-/-).

METHODSSeveral parameters, including blood pressure, renal sodium excretion, D(3) receptor protein and mRNA expression, plasma renin activity, norepinephrine concentration and AT(1) receptor expression were checked in D(3)-/- mice and their littermate wild type mice (D(3)+/+). Moreover, the vasorelaxant effect of D(3) receptor stimulation was measured with ex-vivo mesenteric artery isolated from Wistar-Kyoto rats.

RESULTSBlood pressure was higher in D(3)-/- mice compared with that in D(3)+/+ mice, salt-loading had no effect on blood pressure in both groups, at the last period, sodium excretion was lower in D(3)-/- mice as compared with D(3)+/+ mice, renal renin activity and AT(1) receptor expression were higher in D(3) -/- [corrected] mice than in D(3) +/+ [corrected] mice. In contrast, no difference of renal norepinephrine was found in two groups. When using angiotensin II subtype-1 receptor antagonist, the systolic blood pressure declined for a longer duration in mutant mice than in wild-type mice. Vaso-relaxation was found in ex-vivo isolated mesenteric artery when D(3) receptor was stimulated.

CONCLUSIONSElevation of blood pressure in D(3)-/- mice might be related with impaired renal sodium excretion and vaso-relaxation in resistance artery.

Animals ; Hypertension ; genetics ; physiopathology ; Kidney ; Mesenteric Arteries ; physiopathology ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Rats ; Receptors, Dopamine D3 ; genetics

The aim of the studies was to investigate klotho gene effect on the endothelial dysfunction of spontaneously hypertensive rats (SHR). In this study, ten SHR and ten normal Wistar rats, all 22 week old, were prepared. After given intraperitoneal anesthesia, the rats' brains, lungs, hearts, kidneys and aortas were removed. The identification was made by means of real-time polymerase chain reaction (Real-time PCR) and Enzyme-Linked Immunosorbent Assay (ELISA). Compared with the normal group, the klotho mRNA and protein in SHR were less than those in the control group with normal corresponding values, while Endothelin-1 (ET-1)'s mRNA and protein were more than those of normal group. The analysis of the correlation of mRNA and protein in heart and aorta revealed that klotho gene was negatively correlated to ET-1. The results showed that klotho significantly decreased in SHR, which might be influenced by hypertension-induced damage on the endothelial function.
Aging ; genetics ; Animals ; Endothelin-1 ; genetics ; metabolism ; Endothelium, Vascular ; physiopathology ; Glucuronidase ; genetics ; metabolism ; Hypertension ; genetics ; physiopathology ; Male ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Inbred SHR

OBJECTIVETo assess the association of tag single nucleotide polymorphisms (tag SNPs) of chymase gene (CMA1) with essential hypertension in Yi population from Yunnan, China.

METHODSA case-control study was carried out. Four tag SNPs(rs1956921, rs1800876, rs5244 and rs1885108) were genotyped in 303 patients with essential hypertension and 312 healthy controls using polymerase chain reaction - restriction fragment length polymorphism(PCR-RFLP) method.

RESULTSNo significant difference in genotypic and allelic distributions of the four polymorphisms was detected between the two groups(P>0.05), and the same results existed in the females. The frequencies of rs1956921 C allele and a C-T haplotype constructed with rs1956921 and rs5244 were greater in male patients compared with male controls(P<0.01).

CONCLUSIONThe rs1956921 C allele of the CMA1 gene and the C-T haplotype constructed with rs1956921 and rs5244 may be risk factors for essential hypertension in ethnic Yi males from Yunnan.

Adult ; Alleles ; Asian Continental Ancestry Group ; ethnology ; genetics ; Blood Pressure ; China ; ethnology ; Chymases ; genetics ; Essential Hypertension ; Female ; Humans ; Hypertension ; ethnology ; genetics ; physiopathology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide

Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH,and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.
Cell Proliferation ; Cells, Cultured ; Humans ; Hypertension, Pulmonary ; physiopathology ; MicroRNAs ; genetics ; Myocytes, Smooth Muscle ; pathology ; Pulmonary Artery ; pathology ; Vascular Remodeling ; genetics

OBJECTIVETo investigate the effect of heat shock protein 70 (HSP70) on pulmonary arterial pressure and pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH).

METHODSA total of 128 Wistar neonatal rats were randomly divided into HPH model and blank control groups. According to the transfection solution, the HPH model group was further divided into normal saline group, empty virus group (viral vectors marked with a green fluorescent signal and not carrying the target gene), and virus+HSP70 group (viral vectors marked with a green fluorescent signal and carrying the target gene). The HPH model was established by inhalation of nitrogen-oxygen mixture (1.5 L/minutes and 8% oxygen). Pulmonary arterial pressure (mPAP) and the indicators of pulmonary vascular remodeling (MT% and MA%) were measured on days 3, 7, 10, and 14 of hypoxia.

RESULTSOn days 3, 7, and 10 of hypoxia, the normal saline and empty virus groups had significantly enhanced expression of HSP70 compared with the blank control group (P<0.01), and the virus+HSP70 group had significantly higher expression of HSP70 than the blank control, normal saline, and empty virus groups (P<0.01). On day 14 of hypoxia, the expression of HSP70 showed no significant difference between these groups (P>0.05). On days 3, 7, and 10 of hypoxia, the normal saline and empty virus groups showed continuous increases in mPAP compared with the blank control group (P<0.05). There was no significant difference in mPAP between the virus+HSP70 and blank control groups (P>0.05). On day 14 of hypoxia, there was no significant difference in mPAP among three subgroups of the HPH model group (P>0.05), but the mPAP in the three subgroups was significantly higher than in the blank control group (P<0.05). After 7 days of hypoxia, the normal saline and empty virus groups showed significantly higher MT% and MA% than the blank control group (P<0.05), but the two indicators showed no significant differences between the virus+HSP70 and the blank control groups (P>0.05). On day 14 of hypoxia, there were no significant differences in MT% and MA% among three subgroups of the HPH model group (P>0.05), but the MT% and MA% in the three subgroups were higher than in the blank control group (P<0.05).

CONCLUSIONSHSP70 may reduce pulmonary arterial pressure and pulmonary vascular remodeling in neonatal rats with HPH.

Animals ; HSP70 Heat-Shock Proteins ; genetics ; metabolism ; Humans ; Hypertension, Pulmonary ; cerebrospinal fluid ; metabolism ; physiopathology ; Hypoxia ; genetics ; metabolism ; physiopathology ; Oxygen ; metabolism ; Pulmonary Artery ; metabolism ; Rats ; Rats, Wistar ; Vascular Remodeling

The present study was to investigate the mRNA, protein expression and the activity of calcineurin in the hypertrophic heart, and to determine the effect of calcineurin inhibitor--cyclosporine A (CsA) on the regression of cardiac hypertrophy in renovascular hypertensive rats. Renovascular hypertension was induced by two kidney-one clip methods. Two months after the operation, cardiac hypertrophy was determined by histological analysis performed in some rats (2K1C-2M), then the rats were subdivided into 2 groups: (1) 3-month old two kidney-one clip group (2K1C-3M) with rats receiving 0.9% NaCl per day for one month, and (2) CsA-treated group with rats treated with CsA for one month. Sham-operated rats were used as control. The ratio of the left ventricular weight to tibial length (LVW/TL), the area of cardiac myocyte, mRNA and protein expression and the activity of calcineurin were determined. Both the LVW/TL and the cardiomyocyte area were significantly larger in 2K1C-2M and 2K1C-3M rats than in age-matched sham-operated rats. Treatment with CsA significantly attenuated the increase in the LVW/TL as well as the cardiomyocyte area. The mRNA, protein expression and the activity of calcineurin were significantly higher in 2K1C-2M and 2K1C-3M rats than those in the age-matched sham-operated rats, while the elevation of mRNA, protein expression and activity of calcineurin were significantly suppressed in the CsA-treated rats. In conclusion, calcineurin plays a role in the progression of cardiac hypertrophy in renovascular hypertensive rats. The inhibition of calcineurin can reverse cardiac hypertrophy.
Animals ; Calcineurin ; biosynthesis ; genetics ; metabolism ; Cyclosporine ; pharmacology ; Hypertension, Renovascular ; complications ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; etiology ; metabolism ; physiopathology ; RNA, Messenger ; biosynthesis ; genetics ; Rats ; Rats, Sprague-Dawley

Placental development requires extensive angiogenesis and the invasion of the maternal decidua by the trophoblasts. Adequate and organized interaction of vascular endothelial growth factors (VEGF), placenta growth factors (PlGF), and their receptors are essential for a normal development and function of the placenta. In this study, we evaluated the expressions of PlGFs and their receptors, mRNAs by Northern blotting, in situ hybridization and RT-PCR in the normal and pregnancy-induced hypertensive (PIH) placentas. The expression level of PlGF-2 mRNA was lower in the PIH placentas compared to control as assessed by Northern blotting and in situ hybridization. PlGF mRNA was mainly localized to the vasculosyncytial membrane of placental villi and villous stroma. The expression of PlGF receptor-1 (PlGFR-1) was significantly increased in the PIH placentas compared to the normal ones. These results suggest that the alteration of PlGF-2 and PlGFR-1 mRNA expressions in the placenta are related to the pathogenesis of PIH.
Female ; Gene Expression ; Human ; Hypertension/*physiopathology ; In Situ Hybridization ; Placenta/*physiology ; Pre-Eclampsia/*physiopathology ; Pregnancy ; Pregnancy Proteins/*genetics ; RNA, Messenger/analysis ; Vascular Endothelial Growth Factor A/*genetics ; Vascular Endothelial Growth Factor Receptor-1/genetics ; Vascular Endothelial Growth Factor Receptor-2/genetics

We have reported that hypoxia increases the activation of 15-lipoxygenase (15-LO), which converts arachidonic acid (AA) into 15-hydroxyeicosatetraenoic acid (15-HETE) in small pulmonary arteries (PAs). Through inhibition of Kv channels, 15-HETE causes more robust concentration-dependent contraction of PA rings from the hypoxic compared to the normoxic controls. However, the subtypes of Kv channels inhibited by 15-HETE are incompletely understood. The aim of the present study was to identify the contribution of Kv3.4 channel in the process of pulmonary vasoconstriction induced by 15-HETE using the tension studies of PA rings from rat with Kv3.4 channel blocker in tissue bath; to explore the role of vascular endothelium in15-HETE-induced pulmonary vasoconstriction through denuded endothelia of PA rings; and to define the downregulation of 15-HETE on the expression of Kv3.4 channel in cultured pulmonary artery smooth muscle cells (PASMCs) with RT-PCR and Western blot. In the present study, healthy Wistar rats were divided randomly into two groups: Group A with normal oxygen supply and group B with hypoxia. Six days later, the rats were killed. Pulmonary artery rings were prepared for organ bath experiments. Firstly, different concentrations of 15-HETE (10~1 000 nmol/L) were added to the Krebs solution. The isometric tension was recorded using a four-channel force-displacement transducer. Then Kv3.4 channel blocker, 100 nmol/L BDS-I, was added, followed by adding 1 mumol/L 15-HETE, and the isometric tension was recorded. Furthermore, RT-PCR and Western blot were employed to identify the influence of 15-HETE on the expression of Kv3.4 channel in cultured rat PASMCs.The results showed the PA tension was significantly increased both in groups A and B by 15-HETE in a concentration-dependent manner (P<0.05), especially in group B (P<0.05 compared to control); denuded endothelia enhanced 15-HETE concentration-related constrictions in rat PA rings; Kv3.4 channel blocker, BDS-I, significantly decreased the PA ring constriction induced by 15-HETE (P<0.05); the expressions of Kv3.4 mRNA and protein in rat PASMCs were significantly downregulated by 15-HETE (P<0.05). Based on all the information above, we conclude that Kv3.4 channel is involved in vasoconstriction induced by 15-HETE in rat PAs.
Animals ; Cells, Cultured ; Female ; Hydroxyeicosatetraenoic Acids ; pharmacology ; Hypertension, Pulmonary ; physiopathology ; Hypoxia ; physiopathology ; Male ; Muscle, Smooth, Vascular ; cytology ; pathology ; Pulmonary Artery ; cytology ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Shaw Potassium Channels ; antagonists & inhibitors ; genetics ; metabolism ; Vasoconstriction ; drug effects

Pulmonary vascular remodeling is one of the major characteristics of hypoxia-induced pulmonary hypertension, mainly represented by over-proliferation of pulmonary artery smooth muscle cells (PASMCs). Hypoxia inducible factor-1alpha (HIF-1alpha) is a transcription factor which is produced by the cells exposed to hypoxia. HIF-1alpha up-regulates the expression of many hypoxia response genes (HRGs) for the body to adapt to hypoxia and maintain homeostasis. The expression of HIF-1alpha in the PASMCs is remarkably elevated under hypoxic condition and it stimulates the proliferation of PASMCs. In this experiment, we used gene clone technology to design and synthesize two siRNAs based on the sequence of HIF-1alpha mRNA. They were separately subcloned into the plasmid of pGenesil-1 containing U6 promoter. The pGenesil-1 vector of the RNA interference eukaryotic expression vector specific to HIF-1alpha gene was constructed. DNA sequencing of the plasmid verified the successful construction of the HIF-1alpha RNAi. We isolated and cultured the PASMCs of rat. The pGenesil-1 vector was transferred into the PASMCs with METAFECTENE in vitro. The positive cell clones transfected with pGenesil-1 were obtained after being screened with 400 mug/ml G418. These PASMCs were cultured in normoxia and hypoxia. After 48 h, the effects of RNAi on the expression of HIF-1alpha mRNA were detected by RT-PCR. The cellular growth activities were assayed by MTT colorimetry and flow cytometry in vitro. The results showed that for the PASMCs cultured in hypoxia for 48 h, the cell proliferation of blank group and control group were remarkably increased and the HIF-1alpha mRNA expressions were up-regulated, while the cell proliferation of the treatment groups did not increase and the HIF-1alpha mRNA expressions were not up-regulated. In conclusion, we successfully constructed the recombinant plasmid of RNAi and transfected them into the PASMCs in vitro. The RNAi inhibited the expression of HIF-1alpha mRNA in the PASMCs, and subsequently it remarkably suppressed the proliferation of PASMCs in hypoxia. These results indicate that HIF-1alpha plays a pivotal role in PASMC proliferation.
Animals ; Cell Proliferation ; Cells, Cultured ; Cloning, Molecular ; Hypertension, Pulmonary ; physiopathology ; Hypoxia ; physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Male ; Muscle, Smooth, Vascular ; pathology ; Pulmonary Artery ; pathology ; RNA Interference ; RNA, Messenger ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; Rats ; Transfection