Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ß-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.

MG53 protects against contrast-induced acute kidney injury by reducing cell membrane damage and apoptosis.

Mitsugumin 53 (MG53) is a tripartite motif family protein that has been reported to attenuate injury via membrane repair in different organs. Contrast-induced acute kidney injury (CI-AKI) is a common complication caused by the administration of iodinated contrast media (CM). While the cytotoxicity induced by CM leading to tubular cell death may be initiated by cell membrane damage, we wondered whether MG53 alleviates CI-AKI. This study was designed to investigate the effect of MG53 on CI-AKI and the underlying mechanism. A rat model of CI-AKI was established, and CI-AKI induced the translocation of MG53 from serum to injury sites on the renal proximal tubular (RPT) epithelia, as illustrated by immunoblot analysis and immunohistochemical staining. Moreover, pretreatment of rats with recombinant human MG53 protein (rhMG53, 2 mg/mL) alleviated iopromide-induced injury in the kidney, which was determined by measuring serum creatinine, blood urea nitrogen and renal histological changes. In vitro studies demonstrated that exposure of RPT cells to iopromide (20, 40, and 80 mg/mL) caused cell membrane injury and cell death, which were attenuated by rhMG53 (10 and 50 µg/mL). Mechanistically, MG53 translocated to the injury site on RPT cells and bound to phosphatidylserine to protect RPT cells from iopromide-induced injury. In conclusion, MG53 protects against CI-AKI through cell membrane repair and reducing cell apoptosis; therefore, rhMG53 might be a potential effective means to treat or prevent CI-AKI.

DRD4 Mitigates Myocardial Ischemia/Reperfusion Injury in Association With PI3K/AKT Mediated Glucose Metabolism.

Ischemia-reperfusion (I/R) could cause heart irreversible damage, which is tightly combined with glucose metabolism disorder. It is demonstrated that GLUT4 (glucose transporter 4) translocation is critical for glucose metabolism in the cardiomyocytes under I/R injury. Moreover, DRD4 (dopamine receptor D4) modulate glucose metabolism, and protect neurocytes from anoxia/reoxygenation (A/R) injury. Thus, DRD4 might regulate myocardial I/R injury in association with GLUT4-mediated glucose metabolism. However, the effects and mechanisms are largely unknown. In the present study, the effect of DRD4 in heart I/R injury were studied ex vivo and in vitro. For I/R injury ex vivo, DRD4 agonist (PD168077) was perfused by Langendorff system in the isolated rat heart. DRD4 activated by PD168077 improved cardiac function in the I/R-injured heart as determined by the left ventricular developed pressure (LVDP), +dp/dt, and left ventricular end diastolic pressure (LVEDP), and reduced heart damage evidenced by infarct size, the release of troponin T (TNT) and lactate dehydrogenase (LDH). DRD4 activation diminished I/R injury induced apoptosis and enhanced cell viability impaired by I/R injury in cardiomyocyte, showed by TUNEL staining, flow cytometer and CCK8 assay. Furthermore, DRD4 activation did not change total GULT4 protein expression level but increased the membrane GULT4 localization determined by western blot. In terms of mechanism, DRD4 activation increased pPI3K/p-AKT but not the total PI3K/AKT during anoxia/reoxygenation (A/R) injury in vitro. Interestingly, PI3K inhibitor, Wortmannin, blocked PI3K/AKT pathway and depleted the membrane GULT4, and further promoted apoptosis showed by TUNEL staining, flow cytometer, western blot of cleaved caspase 3, BAX and BCL2 expression. Thus, DRD4 activation exerted a protective effect against I/R injury by promoting GLUT4 translocation depended on PI3K/AKT pathway, which enhanced the ability of glucose uptake, and ultimately reduced the apoptosis in cardiomyocytes.

TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation.

Abnormal growth of the intimal layer of blood vessels (neointima formation) contributes to the progression of atherosclerosis and in-stent restenosis. Recent evidence shows that the 18-kDa translocator protein (TSPO), a mitochondrial membrane protein, is involved in diverse cardiovascular diseases. In this study we investigated the role of endogenous TSPO in neointima formation after angioplasty in vitro and in vivo. We established a vascular injury model in vitro by using platelet-derived growth factor-BB (PDGF-BB) to stimulate rat thoracic aortic smooth muscle cells (A10 cells). We found that treatment with PDGF-BB (1-20 ng/mL) dose-dependently increased TSPO expression in A10 cells, which was blocked in the presence of PKC inhibitor or MAPK inhibitor. Overexpression of TSPO significantly promoted the proliferation and migration in A10 cells, whereas downregulation of TSPO expression by siRNA or treatment with TSPO ligands PK11195 or Ro5-4864 (104 nM) produced the opposite effects. Furthermore, we found that PK11195 (10-104 nM) dose-dependently activated AMPK in A10 cells. PK11195-induced inhibition on the proliferation and migration of PDGF-BB-treated A10 cells were abolished by compound C (an AMPK-specific inhibitor, 103 nM). In rats with balloon-injured carotid arteries, TSPO expression was markedly upregulated in the carotid arteries. Administration of PK11195 (3 mg/kg every 3 days, ip), starting from the initial balloon injury and lasting for 2 weeks, greatly attenuated carotid neointima formation by suppressing balloon injury-induced phenotype switching of VSMCs (increased α-SMA expression). These results suggest that TSPO is a vascular injury-response molecule that promotes VSMC proliferation and migration and is responsible for the neointima formation after vascular injury, which provides a novel therapeutic target for various cardiovascular diseases including atherosclerosis and restenosis.

Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis.

Irisin, a myokine, is cleaved from the extracellular portion of fibronectin domain-containing 5 protein in skeletal muscle and myocardium and secreted into circulation as a hormone during exercise. Irisin has been found to exert protective effects against lung and heart injuries. However, whether irisin influences myocardial infarction (MI) remains unclear. In this study we investigated the therapeutic effects of irisin in an acute MI model and its underlying mechanisms. Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery and treated with irisin for 2 weeks after MI. Cardiac function was assessed using echocardiography. We found that irisin administration significantly alleviated MI-induced cardiac dysfunction and ventricular dilation at 4 weeks post-MI. Irisin significantly reduced infarct size and fibrosis in post-MI hearts. Irisin administration significantly increased angiogenesis in the infarct border zone and decreased cardiomyocyte apoptosis, but did not influence cardiomyocyte proliferation. In human umbilical vein endothelial cells (HUVEC), irisin significantly increased the phosphorylation of ERK, and promoted the migration of HUVEC detected in wound-healing and transwell chamber migration assay. The effects of irisin were blocked by the ERK inhibitor U0126. In conclusion, irisin improves cardiac function and reduces infarct size in post-MI mouse heart. The therapeutic effect is associated with its pro-angiogenic function through activating ERK signaling pathway.

Wnt signaling pathways in myocardial infarction and the therapeutic effects of Wnt pathway inhibitors.

Myocardial infarction (MI) is one of the most serious health threats, resulting in huge physical and economic burdens worldwide. Wnt signaling pathways play an important role in developmental processes such as tissue patterning, cell differentiation and cell division. Appropriate regulation of the activities of Wnt signaling pathways is also important for heart development and healing in post-MI heart. Moreover, Wnt pathway inhibitors have been identified as novel antitumor drugs and applied in ongoing clinical trials. This research progress has generated increasing interests for investigating the effects of Wnt pathway inhibitors on MI healing. In this short review, we summarize the roles of Wnt signaling pathways in post-MI heart and the therapeutic effects of Wnt pathway inhibitors on MI, and discuss the underlying mechanisms of Wnt pathway inhibitors in cardiac repairing.

Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium.

BACKGROUND: Cardiovascular complications, especially myocardial infarctions (MIs), are the leading mortality cause in diabetic patients. The transplantation of stem cells into damaged hearts has had considerable success as a treatment for MI, although whether antidiabetic drugs affect the therapeutic efficacy of stem cell transplantation is still unknown. This study aims to understand whether and how metformin, one of the first-line drugs used to treat type 2 diabetes mellitus (T2DM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts. METHODS: A mouse MI model was generated via permanent ligation of the left anterior descending (LAD) coronary artery. MSCs with or without metformin treatment were transplanted after MI in diabetic mice. Echocardiography was used to assess cardiac function and determine cardiac remodeling, and TTC staining was performed to evaluate infarction size. A mouse gavage model was performed to evaluate bone marrow MSCs for flow cytometry assay. RESULTS: Metformin dampened MSC therapeutic efficacy, which increased infarct size and restricted functional cardiac recovery. Specifically, metformin induced the activation of AMP-activated protein kinase (AMPK)-mediated apoptosis through the inhibition of S6K1-Bad-Bcl-xL cell survival signaling, resulting in the upregulated expression of apoptosis-associated proteins and increased MSC apoptosis. Accordingly, counteracting AMPK attenuated metformin-induced apoptosis in MSCs and partially restored their cardioprotective effects in diabetic mice with MI. Furthermore, a decrease in peripheral blood MSCs was found in patients with T2DM who had a metformin medication history. CONCLUSIONS: Our results highlight an unexpected adverse effect of metformin-induced MSC apoptosis through AMPK-mediated mTOR suppression, which is attenuated by an AMPK inhibitor. Moreover, AMPK inhibition may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI in diabetes.

Macrophage migration inhibitory factor triggers vascular smooth muscle cell dedifferentiation by a p68-serum response factor axis.

AIMS: Macrophage migration inhibitory factor (MIF) is an important proinflammatory mediator linked to arterial diseases. Although its inflammatory property such as macrophage recruitment is known for contributing to vascular pathogenesis, the direct effects of MIF on homeostasis and biological function of vascular smooth muscle cell (VSMC) that are crucial for development of arterial abnormalities, are poorly understood. METHODS AND RESULTS: We show that MIF is able to directly induce VSMC dedifferentiation, a pathophysiological process fundamental for progression of various arterial diseases. Mechanistically, MIF suppresses p68 protein, a crucial regulator of cell growth and organ differentiation, via activation of JNK and p38 MAPKs. siRNA targeting of p68 facilitated dedifferentiation state in VSMCs, whereas p68 overexpression blocked MIF-elicited transition. In addition, MIF decreased the expression of serum response factor (SRF) that governs VSMC differentiation marker genes transcription, through repression of p68 protein. Furthermore, we showed a previously uncharacterized molecular interaction between p68 and SRF by co-immunoprecipitation assay. p68 attenuated MIF-elicited suppression of SRF recruitment to VSMC-specific promoter. Finally, anti-MIF treatment could reverse VSMC dedifferentiation, preserve vascular function, and inhibit remodelling due to vascular injury. CONCLUSIONS: Our results demonstrate a novel mechanism for the regulation of VSMC differentiation by MIF involving p68 and SRF. Strategy for targeting of MIF could inhibit aberrant transition of VSMC in cardiovascular pathogenesis, and may be of therapeutic benefit in phenotype-related arterial remodelling.

Association between insulin dosage and insulin usage time, and coronary artery lesions in patients with type 2 diabetes and coronary heart disease.

Insulin is used in the treatment of type 2 diabetes, with its usage reaching 30-50% in Western countries. The aim of the present study was to determine the association between insulin dosage (ID)/insulin usage time (IT) and coronary artery lesions in patients of type 2 diabetes with coronary heart disease. Based on the insulin using dosage, 353 type 2 diabetes patients were divided into the high-dose (≥0.5 IU/kg) and low-dose (<0.5 IU/kg) group. Selected coronary angiography was performed and the Gensini score was used to determine the degree of the coronary artery lesions. The homeostasis model assessment-insulin sensitivity (HOMA-IS) index was assessed by HOMA2. Data including age, gender, smoking, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), glucose (Glu), hemoglobin A1c (HbA1c), C-peptide, ID, IT, diabetes duration time (DT), and IT/DT were collected. The association between insulin usage (both dose and time) and the coronary artery lesions in these patients was then determined. Statistical differences for the two groups for factors including C-peptide, HbA1c, ID, IT, DT, IT/DT and the Gensini score values (P<0.05) were identified. By contrast, no significant differences for factors such as gender, smoking history, age, BMI, TC, TG, LDL, HDL, fasting insulin, Glu, SBP and DBP were observed. The coronary artery damage Gensini score in insulin-insensitive individuals was significantly greater than that in the insulin-sensitive individuals. The Spearman analysis revealed that ID and IT, DT and IT/DT were positively correlated with the coronary artery damage Gensini score. The multivariate regression, the interquartile range method and receiver operating characteristic analyses showed that ID, ID/DT, IT had a greater effect on coronary vascular damage compared with DT. In conclusion, the degree of coronary artery lesions were correlated with ID, IT, DT, IT/DT. High doses of insulin or a high IT/DT ratio may aggravate coronary artery damage.

Tea consumption and risk of type 2 diabetes mellitus: a systematic review and meta-analysis update.

OBJECTIVE: Tea has been suggested to decrease blood glucose levels and protect pancreatic ß cells in diabetic mice. However, human epidemiological studies showed inconsistent results for the association between tea consumption and type 2 diabetes mellitus (T2DM) risk. The aim of this study was to conduct a meta-analysis to further explore the association between tea consumption and incidence of T2DM. DESIGN: Systematic review and meta-analysis. METHODS: We performed a systematic literature search up to 30 August 2013 in PubMed, EMBASE, Chinese Wanfang Database and CNKI database. Pooling relative risks (RRs) were estimated by random-effect models. Two kinds of subgroup analyses (according to sex and regions) were performed. Sensitive analyses were performed according to types of tea. RESULTS: Overall, no statistically significant relationship between tea consumption and risk of T2DM was found based on 12 eligible studies (pooling RR 0.99, 95% CI 0.95 to 1.03). Compared with the lowest/non-tea group, daily tea consumption (≥3 cups/day) was associated with a lower T2DM risk (RR 0.84, 95% CI 0.73 to 0.97). Subgroup analyses showed a difference between men and women. Overall, the RRs (95% CI) were 0.92 (0.84 to 1.00) for men, and 1.00 (0.96 to 1.05) for women, respectively. Tea consumption of ≥3 cups/day was associated with decreased T2DM risk in women (RR 0.84, 95% CI 0.71 to 1.00). Overall, the RRs (95% CIs) were 0.84 (0.71 to 1.00) for Asians, and 1.00 (0.97 to 1.04) for Americans and Europeans, respectively. No obvious change was found in sensitivity analyses. CONCLUSIONS: The results suggest that daily tea consumption (≥3 cups/day) is associated with a lower T2DM risk. However, further studies are needed to enrich related evidence, especially with regard to types of tea or sex.

[Effects of lipid-modulation and antiplatelet treatment on the endothelial lipase expression].

OBJECTIVE: To investigate the effects of lipid-modulation and antiplatelet treatment on the expression of endothelial lipase (EL) of patients with coronary artery disease (CAD), and investigate the role of EL in the development of CAD. METHODS: One hundred and fifty-seven cases were divided into three groups according to clinical manifestations and the results of coronary artery angiography: control group (n=41) with more than one risk factors of CAD and the vessel lesions was <30%; stable angina pectoris (SAP) group (n=55); acute coronary syndrome (ACS) group (n=61). The EL positive cell rate was measured 2 weeks after cessation of lipid-modulation and aspirin treatment, and 6 months after treatment with simvastatin and/or aspirin. The drug was ceased for the complications or not tolerance for the treatment. RESULTS: Except the patients in control group with aspirin treatment, the EL positive cell rate was significantly decreased among other groups [control group with simvastatin: (3.93±0.87)% vs. (5.28±1.05)%, SAP group: (8.16±2.11)% vs. (15.12±2.53)%, ACS group: (13.93±3.22)% vs. (38.44±4.36)%; SAP group with aspirin: (10.57±4.07)% vs. (14.66±2.29)%, ACS group: (18.28±5.14)% vs. (40.27±3.96)%; control group with aspirin and simvastatin: (3.13±0.87)% vs. (5.33±1.25)%, SAP group: (5.68±2.20)% vs. (14.89±2.15)%, ACS group: (7.81±3.96)% vs. (39.27±5.17)%, P<0.05 or P<0.01]. CONCLUSION: The treatment with lipid-modulation and/or antiplatelet drug may significantly decrease the expression of EL, implying that EL participates in the progression of CAD.

An essential role for stromal interaction molecule 1 in neointima formation following arterial injury.

AIMS: There is evidence to suggest that stromal interaction molecule 1 (STIM1) functions as a Ca2+ sensor on the endoplasmic reticulum, leading to transduction of signals to the plasma membrane and opening of store-operated Ca2+ channels (SOC). SOC have been detected in vascular smooth muscle cells (VSMCs) and are thought to have an essential role in the regulation of contraction and cell proliferation. We hypothesized that knockdown of STIM1 inhibits VSMC proliferation and suppresses neointimal hyperplasia. METHODS AND RESULTS: We examined the effect of the knockdown of STIM1 using a rat balloon injury model and cultured rat aortic VSMCs. Interestingly, knockdown of rat STIM1 by adenovirus delivery of small interfering RNA (siRNA) significantly suppressed neointimal hyperplasia in a rat carotid artery balloon injury model at 14 days after injury. The re-expression of human STIM1 to smooth muscle reversed the effect of STIM1 knockdown on neointimal formation. Rat aortic VSMCs were used for the in vitro assays. Knockdown of endogenous STIM1 significantly inhibited proliferation and migration of VSMCs. Moreover, STIM1 knockdown induced cell-cycle arrest in G0/G1 and resulted in a marked decrease in SOC. Replenishment with recombinant human STIM1 reversed the effect of siRNA knockdown. These results suggest STIM1 has a critical role in neointimal formation in a rat model of vascular injury. CONCLUSION: STIM1 may represent a novel therapeutic target in the prevention of restenosis after vascular interventions.

[Study on six-minute walk test and cardiac output response against exercise in patients with chronic heart failure].

OBJECTIVE: To evaluate the significance of cardiac output (CO) response against exercise determined by IGR method and LVEF, 6 MWT distance in patients with chronic heart failure (CHF). METHOD: To adopt 6 MWT, and before and after the test measuring the CO by the IGR method, furthermore, measure LVEF to 36 patients (heart failure group) with CHF, compare with the health groups (control group). RESULTS: The 6MWT distance of heart failure group (333.00 +/- 49.64) m decrease compared with the control group (582.56 +/- 67.97) m (P < 0.01), moreover, the distance of NYHA class III (314.82 +/- 36.27) m is significantly shorter than II (361.57 +/- 55.42) m (P < 0.05). The LVEF of heart failure group (47.0 +/- 0.4)% reduce compared with the control group (66.9 +/- 5.2)% (P < 0.01), and the data of NYHA class III (43.3 +/- 10.3)% is significantly lower than II (52.8 +/- 7.6)% (P < 0.01). The increase in CO response against exercise of heart failure group (5.97 +/- 1.89) L/min decrease compared with control group (8.88 +/- 0.52) L/min (P < 0.01), furthermore, the value of NYHA class III (5.31 +/- 1.52) L/min, compared with II (7.01 +/- 1.98)L/min, is obviously lower (P < 0.01). The 6MWT distance correlates positively with the increase in CO response against exercise (r = 0.63, P < 0.01), but the correlation is not found between the increase CO response against exercise and the LVEF (r = 0.11, P > 0.05). CONCLUSION: Our results show that CO response against exercise measured by IGR method, with the advantages of being noninvasive, safe, convenient and accurate, combining with the 6MWT can evaluate cardiac reserve in patient with CHF.

[G protein kinase 4gammaA142V overexpression induced hypertension by downregulating D1 receptors in transgenic mice].

OBJECTIVE: Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. We investigated the role of G protein kinase (GRK) 4gamma in essential hypertension in GRK4gamma mutant A142V transgenic mice. METHODS: Blood pressure, renal sodium excretion, D(1) receptor protein expression and phosphorylation were measured in GRK4gammaA142V transgenic mice and control mice. Moreover, the effects of GRK4 inhibition by antisense oligonucleotides on D(1) receptor expressions were determined in HK-2 cells. RESULTS: As compared with their control mice, GRK4gammaA142V transgenic mice had higher blood pressure, lower D(1) receptor expression (0.6 +/- 0.2 vs. 1.5 +/- 0.2, P < 0.05), higher D(1) receptor phosphorylation [(65 +/- 7) DU vs. (35 +/- 7) DU, P < 0.05] in renal cortical membranes and the diuretic and natriuretic effects after stimulation of renal D(1) receptor were impaired in GRK4gammaA142V transgenic mice. Inhibition of GRK4 expression (0.60 +/- 0.10 vs. 1.30 +/- 0.09, P < 0.05) by GRK4 antisense oligonucleotides upregulated D(1) receptor expression (1.5 +/- 0.2 vs. 0.8 +/- 0.1, P < 0.05) in HK-2 cells. CONCLUSIONS: Our results show that GRK4gammaA142V overexpression induced hypertension is mediated by dowregulated renal D(1) receptor expressions in GRK4gammaA142V transgenic mice.

[Hypertension in D3 dopamine receptor deficient mice].

OBJECTIVE: To investigate the mechanisms by which hypertension occurs in D(3) dopamine receptor null mice (D(3)-/-). METHODS: Several 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. RESULTS: Blood 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. CONCLUSIONS: Elevation of blood pressure in D(3)-/- mice might be related with impaired renal sodium excretion and vaso-relaxation in resistance artery.