Hormone treatments in congestive heart failure.

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

Total flavonoids from Astragalus alleviate endothelial dysfunction by activating the Akt/eNOS pathway.

Objective To investigate the vasodilative and endothelial-protective effects and the underlying mechanisms of total flavonoids from Astragalus (TFA). Methods The vasodilative activities of TFA were measured with a myograph ex vivo using rat superior mesenteric arterial rings. The primary human umbilical vein endothelial cell (HUVEC) viabilities were assayed using the cell counting kit-8 after hypoxia or normoxia treatment with or without TFA. Akt, P-Akt, eNOS, P-eNOS, Erk, P-Erk, Bcl-2 and Bax expression were analyzed using western blotting. Results TFA showed concentration-dependent vasodilative effects on rat superior mesenteric arterial rings, but had no effects on normal or potassium chloride precontracted arterial rings. TFA did not affect HUVEC viabilities in normoxia, but dramatically promoted cell proliferation in the concentration range of 1 to 30 µg/mL under hypoxia. Moreover, TFA significantly increased the ratios of P-Akt/Akt and P-eNOS/eNOS in vascular endothelial cells under hypoxic conditions, but did not change the P-Erk/Erk or Bcl-2/Bax ratios. Conclusions TFA might exhibit vasorelaxant and endothelial-protective effects via the Akt/eNOS signaling pathway.

The Correlated Factors of Serum CA19-9 Levels in Diabetic Patients.

BACKGROUND: Serum CA19-9 level is a sensitive marker for pancreatic tissue damage; however, its correlation factors are still unclear in diabetic patients. This study was aimed to investigate the correlation factors of serum CA 19-9 levels in these patients. METHODS AND RESULTS: Based on their serum CA19-9 levels, 412 diabetic patients (57 type 1 and 355 type 2) were divided into the negative group (432 cases, CA19-9 37 U /ml) and the positive group (31 cases, CA19-9 ≥ 37 U /ml). The two groups were compared with age, sex, duration of diabetic history, hemoglobin A1c, blood lipid, fasting C-peptide level, and area under the curve C-peptide. The difference was significant between 2 groups in age, hemoglobin A1c, total cholesterol, highdensity lipoprotein cholesterol, fasting C-peptide level, and area under the curve C-peptide (P < 0.05). A multivariate linear regression model found that the type of diabetes, hemoglobin A1c, area under the curve C-peptide, and high-density lipoprotein cholesterol are the independent contributors to CA19-9 levels. CONCLUSION: The results indicated that CA19-9 levels in patients with diabetes mellitus were related to not only age and sex but also diabetic type, hemoglobin A1c, lipid metabolism, and pancreatic beta cell function.

Ghrelin and Blood Pressure Regulation.

Ghrelin is a growth hormone-releasing polypeptide that was first isolated from the rat stomach in 1999. High expression of growth hormone secretagogue receptor, the ghrelin receptor, in the heart, kidney, and blood vessels provides evidence of ghrelin activity in blood pressure regulation. Circulating ghrelin concentrations are reported to be inversely correlated with blood pressure, and the acute and chronic effects of ghrelin in decreasing blood pressure have been reported in animals with normal blood pressure, healthy individuals, animals and patients with heart failure, and animals with hypertension. The mechanism by which ghrelin regulates blood pressure appears to be related to modulation of the autonomic nervous system, direct vasodilatory activities, and kidney diuresis. Thus, modulation of the signaling pathway through ghrelin may provide a novel concept for treating hypertension. In this review, we discuss the current evidence and potential mechanisms of ghrelin activity in blood pressure regulation.

Endogenous ghrelin attenuates pressure overload-induced cardiac hypertrophy via a cholinergic anti-inflammatory pathway.

Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin's ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1ß and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload-induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway.

Impaired regulator of G protein signaling 2 transcription facilitates vascular remodeling in injured rat aorta.

BACKGROUND: The activation of Gq-protein-coupled receptors induces proliferation of vascular smooth muscle cells (VSMCs) proliferation and is involved in vascular remodeling. The regulator of G protein signaling 2 (RGS2), which accelerates the termination of Gq protein signaling, may play a role in vascular remodeling. However, this role remains unclear. METHODS: Aortic balloon injury or sham operation was produced in male Wistar rats. Histological examination and gene expression analysis were performed after surgery. In cultured VSMCs after modulation of RGS2 expression, cell proliferation was also evaluated. RESULTS: At day 3 after injury, RGS2 transcription was reduced by 52.8% (P <0.05 vs. sham group) with vascular remodeling. In cultured VSMCs stimulated by endothelin-1, phenylephrine or angiotensin II, the proliferation of RGS2 overexpressed cells was significantly inhibited; the proliferation of RGS2 downregulated cells was significantly promoted, compared with that of RGS2 normal cells. Moreover, after incubation with angiotensin II of high concentration (>10 µmol/l) or long term (>8 h), the RGS2 expression was clearly downregulated in cultured VSMCs. Administration of an angiotensin receptor blocker, valsartan (20 mg/kg per day) starting from 1 week preballoon injury to 3 days after injury, restored aortic RGS2 transcription and improved vascular remodeling. CONCLUSION: These results suggested that the inhibiting effect of RGS2 on VSMC proliferation is downregulated in vascular remodeling of injured rat aorta, and this effect is likely to be mediated by angiotensin II signaling.

Adrenomedullin and adrenotensin increase the transcription of regulator of G­protein signaling 2 in vascular smooth muscle cells via the cAMP­dependent and PKC pathways.

The regulator of G­protein signaling 2 (RGS2) has been shown to be crucial in the regulation of vascular tone and blood pressure. The vascular activities of adrenomedullin (ADM) and adrenotension (ADT), two natural peptides, are dependent upon the modulation of RGS2 expression. However, the effects and pathways involved in their modulation remain unknown. This study aimed to observe the changes of RGS2 expression in response to ADM and ADT in cultured vascular smooth muscle cells and to clarify the potential signaling pathways in vitro. In the present study, vascular smooth muscle cells (VSMCs) were cultured with ADM and ADT of various concentrations for different time periods, and the gene expression of RGS2 was analyzed by PCR. ADM significantly increased the gene expression at 0.5 h to ~35­fold of that at baseline, whereas ADT marginally increased the expression after 1­2 h. SQ22,536 and chelerythrine were used to block the protein kinase A (PKA) and PKC pathways activated by incubation with ADM. The gene expression of RGS2 was reduced by SQ22,536 only. Furthermore, when SQ22,536 and chelerythrine were added to the cells incubated with ADT, the gene expression was markedly reduced by both SQ22,536 and chelerythrine. In conclusion, ADM immediately showed a marked increase in the gene expression of RGS2 in cultured VSMCs via a cAMP­dependent pathway and ADT gradually showed a marginal increase in the gene expression via a cAMP­dependent pathway and a PKC pathway.

Excessive sympathoactivation and deteriorated heart function after myocardial infarction in male ghrelin knockout mice.

We have previously demonstrated the protective role of endogenous ghrelin against malignant arrhythmias in the very acute phase of myocardial infarction (MI). However, the role of endogenous ghrelin in the chronic phase is unknown. Therefore, the aim of the current study was to focus on the effects of endogenous ghrelin on cardiac function and sympathetic activation after acute MI. In 46 ghrelin-knockout (KO) and 41 wild-type (WT) male mice, MI was produced by left coronary artery ligation. The mortality due to heart failure within 2 weeks was 0% in WT and 10.9% in KO (P < 0.05). At the end of this period, lung weight/tibial length, atrial natriuretic peptide and brain natriuretic peptide transcripts, end-systolic and end-diastolic volumes were all significantly greater in KO mice, whereas systolic function, represented by ejection fraction (16.4 ± 4.7% vs 25.3 ± 5.1%), end-systolic elastance, and preload-recruitable stroke work, was significantly inferior to that in WT mice (P < 0.05). Telemetry recording and heart rate variability analysis showed that KO mice had stronger sympathetic activation after MI than did WT mice. Metoprolol treatment and ghrelin treatment in KO mice prevented excessive sympathetic activation, decreased plasma epinephrine and norepinephrine levels, and improved heart function and survival rate after MI. Our data demonstrate that endogenous ghrelin plays a crucial role in protecting heart function and reducing mortality after myocardial infarction, and that these effects seem to be partly the result of sympathetic inhibition.

Diabetic nephropathy is associated with prostate-specific antigen levels in type 2 diabetes mellitus.

PURPOSE: Type 2 diabetes is associated with reduced risk of prostate cancer and low prostate-specific antigen levels for uncertain reasons. Recently, two studies demonstrated the time course of diabetes with prostate-specific antigen levels, which would be explained by the chronic renal complication. Therefore, we conducted a retrospective study to determine whether diabetic nephropathy is associated with prostate-specific antigen levels. METHODS AND RESULTS: Eligible patients were men aged ≥40 years, with type 2 diabetes and a recorded prostate-specific antigen level. Patients with a prior history of prostate cancer or prostatectomy or prostate-specific antigen level ≥10 ng/mL and patients with end-organ damage were excluded. Of the 247 patients included in the adjusted analysis, 51 (20.8 %) were diagnosed with diabetic nephropathy. A significant association of diabetic nephropathy with log-transformed prostate-specific antigen level was detected (Spearman's correlation coefficient -0.201, p = 0.003; adjusted for all other correlated variables) and fit into a linear regression model (B-coefficient -0.331, p = 0.003). Comparing diabetic nephropathy group with non-diabetic nephropathy group, the difference in log-transformed prostate-specific antigen levels was also significant (p = 0.002). CONCLUSION: The results indicated that patients with diabetic nephropathy have low prostate-specific antigen levels, suggesting fewer prostate cancers being detected or fewer incidences among this group.

Ghrelin prevents incidence of malignant arrhythmia after acute myocardial infarction through vagal afferent nerves.

Ghrelin is a GH-releasing peptide mainly excreted from the stomach. Ghrelin administration has been shown to inhibit cardiac sympathetic nerve activity (CSNA), reduce malignant arrhythmia, and improve prognosis after acute myocardial infarction (MI). We therefore investigated the effects and potential mechanisms of the action of endogenous ghrelin on survival rate and CSNA after MI by using ghrelin-knockout (KO) mice. MI was induced by left coronary artery ligation in 46 KO mice and 41 wild-type mice. On the first day, malignant arrhythmia-induced mortality was observed within 30 min of the ligation and had an incidence of 2.4% in wild-type and 17.4% in KO mice (P < 0.05). We next evaluated CSNA by spectral analysis of heart rate variability. CSNA, represented by the low frequency/high frequency ratio, was higher in KO mice at baseline (2.18 ± 0.43 vs. 0.98 ± 0.09; P < 0.05), and especially after MI (25.5 ± 11.8 vs. 1.4 ± 0.3; P < 0.05), than in wild-type mice. Ghrelin (150 µg/kg, s.c.) 15 min before ligation suppressed the activation of CSNA and reduced mortality in KO mice. Further, this effect of ghrelin was inhibited by methylatropine bromide (1 mg/kg, i.p.) or by perineural treatment of both cervical vagal trunks with capsaicin (a specific afferent neurotoxin). Our data demonstrated that both exogenous and endogenous ghrelin suppressed CSNA, prevented the incidence of malignant arrhythmia, and improved the prognosis after acute MI. These effects are likely to be via the vagal afferent nerves.