Brain Natriuretic Peptide mRNA Research Articles

Dual agonism of peripheral cannabinoid CB1/CB2 receptors suppresses cardiac myocyte hypertrophy (652.9)

The development of endocannabinoid‐based therapies is hindered by psychoactive side effects mediated by central CB1 receptors. We determined the effect of CB‐13, a peripherally‐restricted agonist of CB1/CB2 receptors, on cardiac myocyte hypertrophy. Endothelin‐1 (ET‐1, 0.1 μM) induced hypertrophy of rat cardiac myocytes as measured by cell enlargement (122±4%), protein synthesis ([3H]‐leucine incorporation; 147±13%), and fetal gene expression (brain natriuretic peptide mRNA levels; 426±88%) (p<0.05 vs. controls). CB‐13 attenuated all hypertrophic indicators and activated two anti‐hypertrophic signals: AMP‐activated protein kinase (AMPK) and eNOS through phosphorylation at Thr172 and Ser1177, respectively. eNOS activation was ablated by shRNA knockdown of AMPK, and disruption of signaling through AMPK (knockdown) or eNOS (L‐NIO, 1 μM) blocked the anti‐growth effects of CB‐13. CB‐13 also improved mitochondrial function by trafficking through AMPK and PGC‐1α (a driver of mitochondrial biogenesis). ET‐1‐induced mitochondrial depolarization, as assessed by subcellular compartmentalization of the potential‐sensitive dye, JC‐1, was inhibited by CB‐13. In conclusion, dual agonism of peripheral CB1/CB2 receptors is protective in the context of cardiac myocyte hypertrophy and mitochondrial dysfunction vis‐à‐vis crosstalk between AMPK, eNOS and PGC‐1α.

Abstract 081: Liganded Cannabinoid Receptors Suppress Cardiac Myocyte Hypertrophy by AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) signaling

Endocannabinoids are bioactive lipids that signal through CB1 and CB2 cannabinoid receptors. Despite an effort to avoid the psychoactive side effects mediated by central CB1 receptors, we previously found that selective activation of CB2 receptors is not sufficient to prevent cardiac myocyte hypertrophy. Thus, the objective of this study is to determine the effects of CB13, a peripherally-restricted agonist of CB1/CB2 receptors, on hypertrophy. The effects of CB-13 on endothelin-1 (ET1)-induced hypertrophy were determined using isolated neonatal rat myocytes. Hypertrophic indicators included myocyte enlargement, protein synthesis by [3H]-leucine incorporation, and fetal gene expression as brain natriuretic peptide (BNP) mRNA levels. AMPK and eNOS signaling were assessed by immunoblotting. ET1 increased myocyte size (122±4% vs. control; p<0.01), BNP expression (426±88% vs. control; p<0.01) and [3H]-leucine incorporation (147±13% vs. control; p<0.05). CB13 attenuated all three hypertrophic indicators (respectively, 104±3%, 210±32%, 90±8% vs. control; not significant). We next queried whether the anti-hypertrophic actions of CB13 were mediated by AMPK. CB13 increased total expression (222±45% vs. control; p<0.05) and phosphorylation (354±58% vs. control; p<0.01) of AMPK. Also, pretreatment with a chemical inhibitor of AMPK, compound C, attenuated the anti-hypertrophic actions of CB-13. AMPK is a regulator of cellular energy, so we determined that ET-1-induced mitochondrial depolarization, as assessed using the potential-sensitive dye, JC-1, was prevented by CB-13. In addition, CB-13 increased eNOS phosphorylation (237±51%; p<0.01), which suggests that AMPK-eNOS crosstalk, through anti-growth nitric oxide signaling, plays a role. These findings support the notion that agonism of CB1 and CB2 receptors by CB13, a synthetic endocannabinoid with poor brain-blood barrier penetration, prevents hypertrophy and mitochondrial dysfunction. These CB13 actions rely on AMPK signaling, and are associated with eNOS activation. In conclusion, cannabinoid-based treatment of heart disease remains a viable goal with therapeutic potential and warrants further study.

Mechanistic analysis for time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone levels in 5/6 nephrectomized rats

This study investigates the time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone (PTH) levels in 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency. In this study, 5/6 NX male, Sprague–Dawley rats were treated with vehicle or cinacalcet (10 mg/kg, oral, 1× daily). On Day 0 (before treatment), Day 12 and 13 after treatment (to approximate the clinical practice), and also at 0, 1, 4, 8, 16, and 24 hours after the last dosing, blood was collected for analysis. After 12 or 13 days of cinacalcet treatment, modest changes were observed in serum Ca and phosphorus (Pi), while PTH decreased by >45% to Sham levels (152 ± 15 pg/mL). Detailed mapping found that cinacalcet caused a significant time-dependent decrease in serum Ca following dosing, reaching a lowest point at 8 hours (decrease by 20% to 8.43 ± 0.37 mg/dL), and then returning to normal at 24 hours. Cinacalcet also caused a significant increase in serum Pi levels (by 18%). To investigate the potential mechanism of action, a broad approach was taken by testing cinacalcet in a panel of 77 protein-binding assays. Cinacalcet interacted with several channels, transporters, and neurotransmitter receptors, some of which are involved in brain and heart, and may impact Ca homeostasis. Cinacalcet dose-dependently increased brain natriuretic peptide (BNP) mRNA expression by 48% in cardiomyocytes, but had no significant effects on left ventricular hypertrophy and cardiac function. The results suggest that cinacalcet's hypocalcemic effect may be due to its nonspecific interaction with other receptors in brain and heart.

Celiprolol reduces oxidative stress and attenuates left ventricular remodeling induced by hypoxic stress in mice

We have previously reported that intermittent hypoxic stress, which is relevant to sleep apnea syndrome (SAS), increases oxidative stress and induces left ventricular (LV) remodeling. Celiprolol, a β1-selective adrenoreceptor blocker, is known to have not only an antihypertensive effect but also an antioxidant effect through releasing nitric oxide. The aim of this study was to examine the hypothesis that celiprolol might ameliorate the LV remodeling induced by intermittent hypoxia through its antioxidant effect. Male C57BL/6J mice (8 weeks old) were exposed to intermittent hypoxia (30 s of 5% oxygen followed by 30 s of 21% oxygen) for 8 h day(-1) during the daytime for 10 consecutive days or were maintained under normoxic conditions. Animals were treated with either celiprolol (100 mg kg(-1) day(-1) by gavage) or vehicle. Hypoxic stress caused fluctuations in blood pressure (BP), an increase in the mean cardiomyocyte diameter, perivascular fibrosis and a decrease in endothelial nitric oxide synthase (eNOS) expression. These changes were associated with increased levels of 4-hydroxy-2-nonenal protein, superoxide, tumor necrosis factor-α mRNA and brain natriuretic peptide mRNA in the LV myocardium. Celiprolol significantly suppressed BP fluctuation, restored eNOS expression and reduced oxidative stress and superoxide production, thus ameliorating hypoxia-induced LV remodeling in mice. These findings suggest that treatment with celiprolol might prevent cardiovascular events in borderline hypertensive patients with SAS.

THU0056 A Small Chemical Compound Identified as an ACE2 Activator Prevented Pulmonary Arterial Hypertension Induced by Monocrotaline

BackgroundPulmonary arterial hypertension (PAH) is a lethal clinical symptom characterized by progressive increase in pulmonary arterial pressure and causes right ventricular hypertrophy (RVH) with RV failure. Complications of PAH are...

Mechanical Stretch Increases Brain Natriuretic Peptide Production and Secretion in the Human Fetal Membranes

Brain natriuretic peptide (BNP) is synthesized by human fetal membranes, both the amnion and chorion. This locally produced BNP inhibits the contraction of the human myometrium, contributing to the maintenance of myometrial quiescence during pregnancy. We tested the hypothesis that BNP production is increased by fetal membrane stretching, which is predicted to occur in the expanding uterus, and inhibited by epidermal growth factor (EGF), whose production in the fetal membranes increases in late pregnancy. Term fetal membranes were obtained during elective cesarean delivery before labor. Sections of membranes were placed in an isolated chamber containing DMEM: F12 medium (37°C) and stretched with a 35 g weight. Medium and tissue samples were collected at 0, 3, 6, 18, and 24hours for measurement of messenger RNA (mRNA) and BNP levels in the presence/absence of EGF (2 × 10(-9)mol/L). Inducible nitric oxide synthase (iNOS) and β-actin were also evaluated to discard a nonspecific effect of mechanical stretch on protein expression. We found that amnion and chorion stretching increased the BNP mRNA (reverse transcription-polymerase chain reaction [RT-PCR]) and protein (radioimmunosorbent assay [RIA]) levels from 18 hours onward. The effect of stretching was inhibited by EGF (2 × 10(-9) mol/L). Stretch did not increase iNOS or β-actin protein levels. We concluded that chorion and amnion stretching may increase BNP expression in the fetal membranes during pregnancy, while increasing biological activity of EGF may decrease BNP production in the chorion and amnion late in pregnancy. We postulate BNP is an important regulator of myometrial contractility during pregnancy, and its production is modulated by both stretch and progressive increase in EGF levels during pregnancy.

Rheb (Ras Homologue Enriched in Brain)-dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation Becomes Indispensable for Cardiac Hypertrophic Growth after Early Postnatal Period

Cardiomyocytes proliferate during fetal life but lose their ability to proliferate soon after birth and further increases in cardiac mass are achieved through an increase in cell size or hypertrophy. Mammalian target of rapamycin complex 1 (mTORC1) is critical for cell growth and proliferation. Rheb (Ras homologue enriched in brain) is one of the most important upstream regulators of mTORC1. Here, we attempted to clarify the role of Rheb in the heart using cardiac-specific Rheb-deficient mice (Rheb(-/-)). Rheb(-/-) mice died from postnatal day 8 to 10. The heart-to-body weight ratio, an index of cardiomyocyte hypertrophy, in Rheb(-/-) was lower than that in the control (Rheb(+/+)) at postnatal day 8. The cell surface area of cardiomyocytes isolated from the mouse hearts increased from postnatal days 5 to 8 in Rheb(+/+) mice but not in Rheb(-/-) mice. Ultrastructural analysis indicated that sarcomere maturation was impaired in Rheb(-/-) hearts during the neonatal period. Rheb(-/-) hearts exhibited no difference in the phosphorylation level of S6 or 4E-BP1, downstream of mTORC1 at postnatal day 3 but showed attenuation at postnatal day 5 or 8 compared with the control. Polysome analysis revealed that the mRNA translation activity decreased in Rheb(-/-) hearts at postnatal day 8. Furthermore, ablation of eukaryotic initiation factor 4E-binding protein 1 in Rheb(-/-) mice improved mRNA translation, cardiac hypertrophic growth, sarcomere maturation, and survival. Thus, Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after early postnatal period.

Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker

BackgroundDiabetic cardiomyopathy (DCM) is defined as structural and functional changes in the myocardium due to metabolic and cellular abnormalities induced by diabetes mellitus (DM). The impact of prediabetic conditions on the cardiac tissue remains to be elucidated. The goal of this study was to elucidate whether cardiac dysfunction is already present in a state of prediabetes, in the presence of insulin resistance, and to unravel the underlying mechanisms, in a rat model without obesity and hypertension as confounding factors.MethodsTwo groups of 16-week-old Wistar rats were tested during a 9 week protocol: high sucrose (HSu) diet group (n = 7) – rats receiving 35% of sucrose in drinking water vs the vehicle control group (n = 7). The animal model was characterized in terms of body weight (BW) and the glycemic, insulinemic and lipidic profiles. The following parameters were assessed to evaluate possible early cardiac alterations and underlying mechanisms: blood pressure, heart rate, heart and left ventricle (LV) trophism indexes, as well as the serum and tissue protein and/or the mRNA expression of markers for fibrosis, hypertrophy, proliferation, apoptosis, angiogenesis, endothelial function, inflammation and oxidative stress.ResultsThe HSu-treated rats presented normal fasting plasma glucose (FPG) but impaired glucose tolerance (IGT), accompanied by hyperinsulinemia and insulin resistance (P < 0.01), confirming this rat model as prediabetic. Furthermore, although hypertriglyceridemia (P < 0.05) was observed, obesity and hypertension were absent. Regarding the impact of the HSu diet on the cardiac tissue, our results indicated that 9 weeks of treatment might be associated with initial cardiac changes, as suggested by the increased LV weight/BW ratio (P < 0.01) and a remarkable brain natriuretic peptide (BNP) mRNA overexpression (P < 0.01), together with a marked trend for an upregulation of other important mediators of fibrosis, hypertrophy, angiogenesis and endothelial lesions, as well as oxidative stress. The inflammatory and apoptotic markers measured were unchanged.ConclusionsThis animal model of prediabetes/insulin resistance could be an important tool to evaluate the early cardiac impact of dysmetabolism (hyperinsulinemia and impaired glucose tolerance with fasting normoglycemia), without confounding factors such as obesity and hypertension. Left ventricle hypertrophy is already present and brain natriuretic peptide seems to be the best early marker for this condition.

Elevated Systolic Blood Pressure in Male GH Transgenic Mice Is Age Dependent

Acromegaly is associated with an increased incidence of cardiovascular disease. Transgenic mice expressing bovine GH (bGH) gene have previously been used to examine the effects of chronic GH stimulation on cardiovascular function. Results concerning systolic blood pressure (SBP) in bGH mice are conflicting. We hypothesized that these discrepancies may be the result of the various ages of the mice used in previous studies. In the current study, SBP was assessed monthly in male bGH mice from 3-12 months of age. Factors known to alter blood pressure were assessed during this time and included: levels of brain natriuretic peptide (BNP) and glucose homeostasis markers, and renal levels of angiotensin-converting enzyme 2 and endothelial nitric oxide synthase. Beginning at 6 months of age bGH had increased SBP compared with wild-type controls, which remained elevated through 12 months of age. Despite having increased blood pressure and cardiac BNP mRNA, bGH mice had decreased circulating levels of BNP. Additionally, bGH mice had an age-dependent decline in insulin levels. For example, they were hyperinsulinemic at 3 months, but by 11 months of age were hypoinsulinemic relative to wild-type controls. This decrease in insulin was accompanied by improved glucose tolerance at 11 months. Finally, both angiotensin-converting enzyme 2 and endothelial nitric oxide synthase expression were severely depressed in kidneys of 11-month-old bGH mice. These results indicate that elevated SBP in bGH mice is dependent on age, independent of insulin resistance, and related to alterations in both the natriuretic peptide and renin-angiotensin systems.

TRASTUZUMAB-INDUCED CARDIOTOXICITY: CAN BIOMARKERS AID DIAGNOSIS?

IntroductionHER2-positive breast cancer therapy with Trastuzumab, typically with the anthracycline, Epirubicin, increases survival but may decrease left ventricular ejection fraction (LVEF) asymptomatically; serial echocardiograms are needed. Increased Brain Natriuretic Peptide...

Exogenous nerve growth factor supplementation elevates myocardial immunoreactivity and attenuates cardiac remodeling in pressure-overload rats

It is postulated that supplementation of exogenous nerve growth factor (NGF) might mediate improvement of the cardiac sympathetic nerve function in heart failure (HF). Local intramuscular injection of NGF near the cardiac sympathetic ganglia could influence the innervation pattern, norepinephrine transporter (NET) gene expression, and improve the cardiac remodeling in experimental HF animals. In this study, we injected NGF into the scalenus medius muscles of Sprague-Dawley rats with abdominal aortic constriction (AC). The nerve innervated pattern, left ventricular morphology, and function following injection in rats with AC were investigated respectively by immunohistochemistry and echocardiography. Levels of mRNA expression of NET, growth associated protein 43 (GAP 43), NGF and its receptors TrkA and p75(NTR), and brain natriuretic peptide (BNP) were measured by real-time polymerase chain reaction. The results showed that myocardial NGF mRNA levels were comparable in rats with AC. Short-term supplementation of exogenous NGF raised the myocardial NGF immunoreactivity, but did not cause hyperinnervation and NET mRNA upregulation in the AC rats. Furthermore, myocardial TrkA mRNA was found to be remarkably decreased and p75(NTR) mRNA was increased. Myocardial TrkA downregulation may play a beneficial effect for avoiding the hyperinnervation, and it is reasonable to postulate that p75(NTR) can function as an NGF receptor in the absence of TrkA. Interestingly, local NGF administration into the neck muscles near the ganglia could attenuate cardiac remodeling and downregulate BNP mRNA. These results suggest that exogenous NGF can reach the target tissue along the axons anterogradely, and improve the cardiac remodeling.

Transient prehypertensive treatment in spontaneously hypertensive rats: A comparison of losartan and amlodipine regarding long-term blood pressure, cardiac and renal protection

The aim of this study was to compare the effectiveness of transient prehypertensive treatment with losartan compared with amlodipine in spontaneously hypertensive rats (SHRs) on long-term blood pressure (BP), cardiac and renal protection. SHRs were prehypertensively treated with losartan, amlodipine or saline. Rats were followed up until 46 weeks of age. The left ventricular (LV) geometry and function were assessed by echocardiography. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassay. Ang II type 1 (AT1R) and type 2 (AT2R) receptor protein expression was determined by western blotting. The systolic blood pressure (SBP) in losartan-treated SHRs (SHR-Los) was persistently reduced until 46 weeks of age, but returned to untreated SHR levels in amlodipine-treated SHRs (SHR-Aml) from 30 weeks onwards. Compared to untreated SHRs, the albuminuria excretion in SHR-Los at week 46 was markedly decreased, the plasma, myocardium and renal tissue Ang II and Aldo levels in SHR-Los at week 46 were markedly decreased; AT1R and TGF-β1 protein expression was downregulated and AT2R protein was upregulated. Compared to untreated SHRs, the left ventricular mass index (LVMI) and collagen volume fraction (CVF) in SHR-Los were markedly decreased until week 46, and the left ventricular ejection fraction (LVEF) and cardiac brain natriuretic peptide mRNA expression were improved, whereas similar LVMI and elevated CVF were observed in SHR-Aml, and the LVEF decreased significantly below that of untreated SHRs at week 46, with cardiac BNP mRNA expression increasing slightly. Prehypertensive treatment with losartan was more effective than amlodipine on delaying long-term BP increase and ameliorating cardiac, renal structure and function, which may be related to the permanent attenuation of the circulating and local renin-angiotensin systems.

INSULIN IMPROVES POST-ISCHAEMIC CARDIAC STRUCTURAL AND FUNCTIONAL CHANGES VIA INHIBITING P38 MAPK ACTIVATION AND THUS INCREASING PLASMA BNP LEVEL

ObjectivesInsulin has been shown to possess cardioprotective effect in acute myocardial ischaemia/reperfusion (MI/R). The present study attempted to test whether long term insulin treatment influences adverse prolonged post-ischaemic cardiac structural...

Role of prostaglandin E2 receptors in H9c2 cardiomyocyte hypertrophy induced by prostaglandin E2

Objective To evaluate the role of prostaglandin E2 (EP) receptors in H9c2 cardiomyocyte hypertrophy induced by prostaglandin E2 (PGE2).Methods Primary cultured H9c2 cardiomyocytes were seeded in culture flasks (3 ml/flask) or in 24-well plate (1 ml/hole) or 6-well plate (2 ml/hole) with density of 4 × 104/ml.The cells were randomly divided into 4 groups (n=24 each): control group (group C),PGE2 group,AH6809 (EP1 and EP2 receptor antagonist) group (group A) and GW627368X (EP4 receptor antagonist) group (group G).The cells were continuously cultured for 48 h.PGE2 (final concentration 1 μmol/L) was added to the culture medium in PGE2 group.PGE2 (final concentration 1 μmol/L) and A H6809 (final concentration 10 μmol/L) were added to the culture medium in group A.PGE2 (final concentration 1 μmol/L) and GW627368X (final concentration 10 μmol/L) were added to the culture medium.The cells were then cultured for 48 h in groups PGE2,A and G.Then the cell morphology was observed by using fluorescent microscope.The cell diameter was measured by using the Image J medical image analysis system.Total protein content in the cells was measured with BCA method.The expression of atrial natriuretic peptide (ANP) mRNA and brain natriuretic peptide (BNP) mRNA in the cytoplasm was determined using RT-PCR.Results Compared with group C,the total protein in the cells and cell diameter were significantly increased,and the expression of ANP mRNA and BNP mRNA in the cytoplasm was up-regulated in groups PGE2,A and G (P ＜ 0.05).Compared with group PGE2,the total protein in the cells and cell diameter were significantly decreased,and the expression of ANP mRNA and BNP mRNA in the cytoplasm was downregulated in group G (P ＜ 0.05),and no significant change was found in the parameters mentioned above in group A (P ＞ 0.05).Conclusion EP4 receptor mediates H9c2 cardiomyocyte hypertrophy induced by PGE2 and the effect is not related to EP1 and EP2. Key words: Dinoprostone; Myocytes,cardiac; Mast cells

Hypoxia stimulates the synthesis and release of Brain Natriuretic Peptide (BNP) in RPE cells

AbstractPurpose Blood flow and oxygen availability of the retina are modulated by locally produced peptides that also can change the function of neurons. The natriuretic peptide system has been isolated and characterized in human retina and these peptides localize in retinal pigment epithelium (RPE) cells. A high concentration of natriuretic peptides has been previously measured from the vitreous of patients suffering of proliferative diabetic retinopathy (PDR). However, the stimulus to which the natriuretic peptide system responds in PDR has remained unknown. We hypothesized that hypoxic conditions will increase the synthesis and release of Brain Natriutretic peptide (BNP) from human RPE cell culture.Methods Human RPE cell were exposed to hypoxia for several hours. Samples were collected at time intervals and analyzed for BNP peptide and for BNP mRNA. A simultaneous measurement of VEGF served as a positive control.Results In hypoxic conditions RPE cells secreted statistically significant amounts of BNP.Conclusion These findings characterize for the first time a stimulus for the natriuretic peptide system in the retina and explain previous clinical findings. Thus, the measurement of natriuretic peptides from the vitreous may guide the treatment of the intraocular diseases in which the retina is suffering from hypoxia.

Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodelling in oophorectomized mRen2.Lewis rats

GPR30 is a novel oestrogen receptor expressed in various tissues, including the heart. We determined the role of GPR30 in the maintenance of left ventricular (LV) structure and diastolic function after the surgical loss of ovarian hormones in the female mRen2.Lewis rat, a model emulating the cardiac phenotype of the post-menopausal woman. Bilateral oophorectomy (OVX) or sham surgery was performed in study rats; the selective GPR30 agonist, G-1 (50 µg/kg/day), or vehicle was given subcutaneously to OVX rats from 13-15 weeks of age. Similar to the cardiac phenotype of sham rats, G-1 preserved diastolic function and structure relative to vehicle-treated OVX littermates independent of changes in blood pressure. G-1 limited the OVX-induced increase in LV filling pressure, LV mass, wall thickness, interstitial collagen deposition, atrial natriuretic factor and brain natriuretic peptide mRNA levels, and cardiac NAD(P)H oxidase 4 (NOX4) expression. In vitro studies showed that G-1 inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, evidenced by reductions in cell size, protein content per cell, and atrial natriuretic factor mRNA levels. The GPR30 antagonist, G15, inhibited the protective effects of both oestradiol and G-1 on this hypertrophy. These data show that the GPR30 agonist G-1 mitigates the adverse effects of oestrogen loss on LV remodelling and the development of diastolic dysfunction in the study rats. This expands our knowledge of the sex-specific mechanisms underlying diastolic dysfunction and provides a potential therapeutic target for reducing the progression of this cardiovascular disease process in post-menopausal women.

Acute myocardial ischaemia directly modulates the expression of brain natriuretic peptide at the transcriptional and translational levels via inflammatory cytokines

Cardiomyocyte stretching has been reported to be a major trigger for brain natriuretic peptide (BNP) release; however, an increase in circulating BNP is observed in patients with acute myocardial ischaemia...

Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

BackgroundProgressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI.MethodsSprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed.ResultsVildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model.ConclusionVildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.

Acute myocardial ischemia directly modulates the expression of brain natriuretic peptide at the transcriptional and translational levels via inflammatory cytokines

Cardiomyocyte stretching has been reported to be a major trigger for brain natriuretic peptide (BNP) release; however, an increase in circulating BNP is observed in patients with acute myocardial ischemia in the absence of increased left ventricular wall stress or cardiomyocyte stretching. In the present study, to investigate the direct and independent effects of acute myocardial ischemia on BNP expression and its mechanism, we established an in vitro glucose-free ischemia and hypoxia injured model of cultured rat cardiomyotes and proved hypoxia upregulated expressions of interleukin-6(il-6) and BNP. Further treatment with il-6 elicited dose- and time-dependent increases in BNP mRNA and protein expression as well as an upregulation in transforming growth factor-β1 (TGF-β1)/Smad2 expression, which was partially suppressed by a neutralizing antibody. In conclusion, our study showed that acute myocardial ischemia can directly upregulate BNP expression at the translational and transcriptional levels through the action of il-6, and this process is associated with the upregulation of TGF-β1/Smad2 signal path.

Gene transfer of the sarcoplasmic reticulum pump in the treatment of heart failure

This editorial refers to ‘Augmentation of left ventricularmechanics by recirculation-mediated AAV2/1-SERCA2agene delivery in experimental heart failure’ by JustinMariani et al. published in this issue on page 247–253.Therapy of congestive heart failure was revolutionized more than20 years ago by the introduction of angiotensin-convertingenzyme inhibitors and b-adrenoceptor blocking agents. Bothhave resulted in the improvement of symptoms and prognosis ofpatients with chronic heart failure. In the meantime, device-basedtherapies have been added to the therapeutic armamentarium.However, all attempts to directly address molecular alterations rel-evant to heart failure pathophysiology as treatment strategies havefailed. Because morbidity and mortality of heart failure patients arestill unacceptably high, there is an urgent need for new treatmentstrategies. Alterations of calcium cycling have been identified as asignificant contributor to heart failure pathophysiology, and there-fore, therapeutic strategies addressing calcium homeostasis seemlogical.