New research advances in relationship of endoplasmic reticulum stress and cardiovascular diseases / 生理学报

Endoplasmic reticulum (ER) is an important organelle for protein folding, post-transcriptional modification and transport, which plays an important role in maintaining cell homeostasis. A variety of internal and external environmental stimuli can cause the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum, and then result in ER stress. ER stress activates the unfolded protein response (UPR) and initiates a cluster of downstream signals to maintain ER homeostasis. However, severe and persistent ER stress activates UPR, which eventually leads to apoptosis and diseases. In recent years, a lot of researches suggest that ER stress plays an important role in the pathogenesis of various cardiovascular diseases (CVD), including ischemic heart disease, diabetic cardiomyopathy, heart failure, atherosclerosis and vascular calcification, high blood pressure and aortic aneurysm. ER stress might be one of the important targets for treatment of multiple CVD. Herein, the regulation mechanism of ER stress by activating UPR pathways in various common CVD and the new research advances in relationship of ER stress and CVD are briefly reviewed.

Protection Effect of Exogenous Fibroblast Growth Factor 21 on the Kidney Injury in Vascular Calcification Rats / 中华医学杂志(英文版)

<p><b>Background</b>Chronic kidney disease (CKD) is closely related to the cardiovascular events in vascular calcification (VC). However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 (FGF21) is an endocrine factor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases. Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats.</p><p><b>Methods</b>The male Sprague-Dawley rats were divided into three groups: (1) control group, (2) Vitamin D3 plus nicotine (VDN)-induced VC group, (3) FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases (ALPs) activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of β-Klotho and FGF receptor 1 (FGFR1) protein were measured by enzyme-linked immunosorbent assay (ELISA). The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining.</p><p><b>Results</b>The renal function impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% (34.750 ± 4.334 μmol/L vs. 27.630 ± 2.387 μmol/L) and 4.0% (7.038 ± 0.590 mmol/L vs. 6.763 ± 0.374 mmol/L; P < 0.01), respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% (P < 0.01) and 11.7% (P < 0.05) as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. ELISA assays showed that the expression of β-Klotho, a component of FGF21 receptor system, was increased in VDN-treated VC rats by 37.4% (6.588 ± 0.957 pg/mg vs. 9.054 ± 0.963 pg/mg; P < 0.01), indicating an FGF21-resistant state. Moreover, FGF21 treatment downregulated the level of β-Klotho in renal tissue by 16.7% (9.054 ± 0.963 pg/mg vs. 7.544 ± 1.362 pg/mg; P < 0.05). However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration (0.191 ± 0.0376 ng/mg vs. 0.189 ± 0.032 ng/mg vs. 0.181 ± 0.034 ng/mg; P > 0.05).</p><p><b>Conclusions</b>In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting off the vicious circle between VC and kidney injury.</p>

Cardiovascular effects of intermedin1-53 and its mechanism / 中国应用生理学杂志

<p><b>AIM</b>The present study was designed to determined the cardiovascular effects of IMD1-53 in rats and its possible mechanism.</p><p><b>METHODS</b>Isolated rat hearts were perfused by Iangendorff mode, and ventricular function was measured after IMD1-53 perfusion. Meanwhere, we investigated the effects of IMDI) on arterial pressure after intravenous administration of IMD. And cAMP content was detected in rat ventricular and aortic tissues.</p><p><b>RESULTS</b>The results showed that perfusion with IMD significantly enhanced cardiac function and resulted in higher LVSP, +dp/dt(max) and -dp/dt(max) by 45%, 51% and 37%, respectively, compared with control and increased coronary infusion flow. The effects of IMD1-53 on cardiac function were antagonized by H-89, an inhibitor of PKA. The content of cAMP in the ventricular tissues after IMD perfusion was 131% higher than control. In addition, intravenous administration of IMD induced a potent decrease in arterial pressureand heart rate, and in aortic tissues, IMD incubation resulted in a 236% increase in cAMP content compared with control group.</p><p><b>CONCLUSION</b>The study reveals that IMD can increase cardiac function and decrease arterial pressure in rat and the effects may be related to cAMP pathway.</p>

Changes of intermedin/adrenomedullin 2 and its receptors in the right ventricle of rats with chronic hypoxic pulmonary hypertension / 生理学报

The purpose of the present study was to explore the expression changes of intermedin/adrenomedullin 2 (IMD/ADM2), a novel small molecular bioactive peptide, and its receptors, calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMP1, RAMP2, RAMP3) in the right ventricle of rats with chronic hypoxia-induced pulmonary hypertension. Twenty male Sprague-Dawley rats were randomly divided into 4-week hypoxia group and normal control group (each n=10). The rats in hypoxia group were placed in an isobaric hypoxic chamber, in which O(2) content was maintained at 9%-11% by delivering N(2), and CO(2) content was maintained at <3% for 4 weeks (8 h/d, 6 d/week). The rats in the control group were housed in room air. The protein levels of IMD/ADM2 and adrenomedullin (ADM) in blood plasma and right ventricular tissue were measured by radioimmunoassay. The mRNA expressions of IMD/ADM2, ADM and their receptors CRLR, RAMP1, RAMP2, RAMP3 in right ventricular tissue were determined by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the ratio of right ventricle weight to left ventricle plus septum weight [RV/(LV+S)] and mean pulmonary arterial pressure (mPAP) were higher in hypoxia group than those in the control group (all P<0.01), suggesting that the rat model of pulmonary hypertension was successfully established. However, the mean carotid arterial pressure (mCAP) between the two groups had no significant difference. Compared with that in the control group, ADM contents in plasma and right ventricular tissue in hypoxia group increased by 1.26 and 1.68 folds (all P<0.01), respectively. Likewise, IMD/ADM2 contents in blood plasma and right ventricular tissue in hypoxia group increased by 0.90 and 1.19 folds (P<0.01), respectively, compared with that in the control group. The data of RT-PCR showed that mRNA levels of ADM, IMD/ADM2 and RAMP2 in hypoxia group increased by 155.1% (P<0.01), 80.9% (P<0.01) and 52.9% (P<0.05), respectively, compared with those in the control group. There were no significant differences in mRNA expressions of CRLR, RAMP1 and RAMP3 between the two groups (all P>0.05). Taken together, the results show that the level of IMD/ADM2 increases in the rats with chronic hypoxia-induced pulmonary hypertension.

The effect of angiotensin-converting enzyme inhibitors and aldosterone receptor blockers on cardiac function in calcium-overload rats / 中国应用生理学杂志

<p><b>AIM</b>To observe the effect of angiotensin-converting enzyme inhibitors (ACEI) and aldosterone receptor blockers on cardiac function to explore the mechanism of cardiac function descending and myocardial injury in calcium-overload rats.</p><p><b>METHODS</b>Calcium-overload in rat was induced by administration of Vitamin D3 plus nicotine. To Estimate the extent of calcium-overload by calcium content. Angiotension II and aldosterone levels in the myocardia were measured by radioimmunoassay. Cardiac function (+/- LVdp/dt, LVESP and LVEDP) were measured by Powerlab. The malondialdehyde (MDA) content, activities of lactate dehydrogenase (LDH) and creatine kinase (CPK) were measured by biochemistry.</p><p><b>RESULTS</b>Calcium content increased by 3.2-, 5.8 -fold in myocardial and artery, compared with controls. VDN-treated survivors showed lower + LVdp/dt(max) and -LVdp/dt(max) values, by 27% and 34%, respectively (both P < 0.01). Higher LVESP, and LVEDP by 42 % and 32% (P < 0.01); heart rate and mean arterial pressure were not significantly altered (P > 0.05). The lipid peroxidation products MDA and conjugated diene in myocardia were increased 22% (P < 0.01), 68% (P < 0.05) (P < 0.05), respectively. The plasma activity of CPK and LDH was greatly increased by 4.5-and 3.1-fold (P < 0.01), respectively. ACEI and spironolactone obviously relieved degree of calcium-overload and improved cardiac function and myocardial injury(P < 0.01). Calcium content in myocardia and artery was lower 44%, 39% and 57%, 34%. Lower MDA by 20%, 30%, lower conjugated diene by 44%, 35% than calcium-overload group. The plasma activity of CPK and LDH were obviously decreased 28%, 34% and 20%, 27%, compared with calcium-overload group.</p><p><b>CONCLUSION</b>Calcium-overload could lead to cardiac function descending and myocardial injury in calcium-overload rats by VDN. ACEI and spironolactone could reduce calcium-overload in myocardial and ameliorate cardiac function and decrease myocardial injury.</p>

Role of adiponectin and its receptors in anti-atherosclerotic effects of pioglitazone on ApoE knocked out mice / 北京大学学报(医学版)

Objective:To study the effects of pioglitazone on atherosclerosis on ApoE-/-mice,and to investigate the roles of adiponectin and its receptors.Methods:ApoE-/-mice were fed with high-fat chow for the induction of atherosclerosis and were divided into three subgroups:placebo(n=10),low-dose[10 mg/(kg?d),n=10] pioglitazone therapy,and high-dose[20 mg/(kg?d),n=10] pioglitazone therapy.C57BL/6J wild type mice(n=9) were used as control.Aortic atherosclerosis and intima-media thickness(intima-media thickness,IMT) of abdominal aorta were monitored,and plasma adiponectin was also measured.Expression levels of the adiponectin receptor 1(AdipoR1)and adiponectin receptor 2(AdipoR2) in vessels were analyzed(RT-PCR).Results:(1) Aortic atherosclerotic lesions were observed in ApoE-/-mice but not in wild type mice.Interestingly,these lesions were significantly prevented by high-dose pioglitazone therapy.Compared with wild type mice,ApoE-/-mice had increased IMT of abdominal aorta [(0.290?0.063 vs 0.178?0.012) cm,P

Levels of adrenomedullin and proadrenomedullin N-terminal 20 peptide in myocardium and aorta of spontaneously hypertensive rats and Wistar-Kyoto rats / 生理学报

In this study, we observed the levels of adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) in myocardium and aorta of spontaneously hypertensive rats (SHRs) in comparison with Wistar-kyoto (WKY) rats. Contents of ADM and PAMP were measured by radioimmunoassay (RIA) in plasma, myocardium and aorta. The amount of Pro-ADM mRNA of myocardium and aorta was determined by competitive quantitative reverse transcription polymerase chain reaction (RT-PCR). In SHRs the amounts of Pro-ADM mRNA of myocardium and aorta were 66.7% (P<0.01) and 73% (P<0.01) higher than those in WKY rat, respectively. In SHRs, the levels of ADM in plasma, myocardium and aorta were 29%, 76.7% and 79% (all P<0.01) higher than those in WKY rats, respectively. The level of PAMP in SHRs was increased by 42.5% in plasma (P<0.01), 47.2% in myocardium (P<0.0.1) and 27.3% in aorta (P<0.05) compared to WKY rats, respectively. In addition, the ratio of ADM content to PAMP content in SHRs group was increased compared with that in WKY group (2.0+/-0.25 vs 1.64+/-0.3 and 2.2+/-0.18 vs 1.56+/-0.28, in myocardium and aorta, respectively, P<0.01). These results suggest that ProADM gene expression is up-regulated and the increase in ADM and PAMP is different in SHRs. The significance of inconsistency of increase in ADM and PAMP in SHRs needs to be further investigated.

Effects of mitochondrial L-arginine/nitric oxide system on mitochondrial Ca2+ transport in rat myocardium / 中国应用生理学杂志

<p><b>AIM AND METHODS</b>To observe the effect of myocardial mitochondrial L-arginine (L-Arg)/nitric oxide (NO) system on mitochondrial Ca2+ transport by using purified rat mitochondria and incubation of them in vitro.</p><p><b>RESULTS</b>Compared with control group, incubation of mitochondria with L-Arg (10(-4) mol/L, NO substrate) or sodium nitroprusside (5 x 10(-7) mol/L, the donor of exogenous NO, SNP) increased significantly mitochondrial NO2- (66% and 89%, P < 0.01), respectively, and decreased the Ca2+ content (40% and 54%, P < 0.01). After L-Arg or SNP treatment, mitochondrial Ca2+ uptake were decreased by 67% and 85%, respectively (P < 0.01), vs control. The rate of mitochondrial Ca2+ release decreased by 11% and 8%, respectively (P < 0.01). When L-NAME (NO synthase inhibitor) was incubated with mitochondria and the L-Arg together, it inhibited the effects of L-Arg, NO2 on the mitochondrial NO2 formation, Ca2+ content descending, and decrease of Ca2+ uptake and release.</p><p><b>CONCLUSION</b>The data suggest that myocardial mitochondrial L-Arg /NO systems take part in the regulation of cardiomyocytes Ca2+ transportation.</p>

Changes in adrenomedullin and receptor activity-modifying protein 2 mRNA in myocardium and vessels during L-NNA-induced hypertension in rats / 生理学报

To explore the changes in adrenomedullin (ADM) and receptor activity-modifying protein 2 (RAMP2) mRNA in myocardium and vessels in hypertension, a hypertensive rat model was prepared by administering L-NNA. Contents of ADM in plasma, myocardium and vessels were measured by radioimmunoassay (RIA). The levels of pro-ADM mRNA of myocardium and vessels were determined by competitive quantitative RT-PCR. The results showed that L-NNA induced hypertension and cardiomegaly. The ratio of heart to body weight increased by 35.5% (P<0.01). In hypertensive rats the ir-ADM in plasma, myocardium and vessels was increased by 80%, 72% and 57% (P<0.01), respectively compared with the control. The amounts of ADM mRNA in myocardium and vessels were increased by 50% and 109.2% (P<0.05), respectively, and the amounts of RAMP2 mRNA was increased by 132% and 87% (P<0.01), respectively, compared with control. The levels of ADM in myocardium and vessels were positively correlated with RAMP2 mRNA, the correlation coefficients were 0.741 and 0.885 (P<0.01), respectively. The results obtained indicate that in hypertensive rats, ADM is elevated in plasma, myocardium and ves-myocardium and vessel, and ADM and RAMP2 mRNA are up-regulated in myocardium and vessel. The ADM/RAMP2 system may play an important role in the pathogenesis of hypertension.

Dysfunction of myocardial and vascular taurine transport in spontaneously hypertensive rats / 生理学报

The alterations of taurine transport and the expression of taurine transporter (TAUT) mRNA in myocardium and aortic wall were investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. It was demonstrated that plasma taurine concentration and taurine release from myocardium and aortic wall in SHR were higher than those in WKY rats, whereas taurine content, taurine uptake and TAUT mRNA in myocardium and aortic wall of SHR were lower than those of WKY rats. In SHR, the maximal velocity (V(max)) of taurine transportation in myocardium and aortic wall was lower by 24% (P<0.05) and 35% (P<0.05) than that in WKY, their michaelis constants (Km) values were higher by 16% (P<0.05) and 39% (P<0.05), respectively. The results suggest that there is dysfunction of taurine transport in myocardium and aortic wall in SHR, which may be partly resulted from the decrease of TAUT activity and affinity, and down-regulation of TAUT gene expression.

An observation of taurine transport alterations in calcification of myocardial cells in vitro / 中国医学科学院学报

<p><b>OBJECTIVE</b>To observe the alterations of taurine transport, taurine transporter (TAUT) and cysteine sulfinate decarboxylase (CSD) mRNA in the calcification of myocardial cells in vitro.</p><p><b>METHODS</b>3H-taurine measured the amount of taurine uptake. TAUT and CSD mRNA consents were measured using competitive quantitative RT-PCR in cultured and calcified myocardial cells.</p><p><b>RESULTS</b>In calcification of myocardial cells, taurine concentration was decreased by 27% (P < 0.05), taurine uptake was markedly reduced, Vmax reduced by 39% (P < 0.01), there were no statistical significance of Km values between the two groups. TAUT mRNA decreased by 45% (P < 0.01), but CSD mRNA increased by 25% (P < 0.05).</p><p><b>CONCLUSIONS</b>The data suggest that there were impediment of taurine transport in calcification of myocardial cells, as TAUT mRNA level was decreased, but CSD mRNA concentration was improved.</p>