Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis.

Ventricular arrhythmia is the most common cause of sudden cardiac death in patients with myocardial infarction (MI). Fibroblast growth factor 21 (FGF21) has been shown to play an important role in cardiovascular and metabolic diseases. However, the effects of FGF21 on ventricular arrhythmias following MI have not been addressed yet. The present study was conducted to investigate the pharmacological action of FGF21 on ventricular arrhythmias after MI. Adult male mice were administrated with or without recombinant human basic FGF21 (rhbFGF21), and the susceptibility to arrhythmias was assessed by programmed electrical stimulation and optical mapping techniques. Here, we found that rhbFGF21 administration reduced the occurrence of ventricular tachycardia (VT), improved epicardial conduction velocity and shorted action potential duration at 90% (APD90) in infarcted mouse hearts. Mechanistically, FGF21 may improve cardiac electrophysiological remodeling as characterized by the decrease of INa and IK1 current density in border zone of infarcted mouse hearts. Consistently, in vitro study also demonstrated that FGF21 may rescue oxidant stress-induced dysfunction of INa and IK1 currents in cultured ventricular myocytes. We further found that oxidant stress-induced down-regulation of early growth response protein 1 (EGR1) contributed to INa and IK1 reduction in post-infarcted hearts, and FGF21 may recruit EGR1 into the SCN5A and KCNJ2 promoter regions to up-regulate NaV1.5 and Kir2.1 expression at transcriptional level. Moreover, miR-143 was identified as upstream of EGR1 and mediated FGF21-induced EGR1 up-regulation in cardiomyocytes. Collectively, rhbFGF21 administration effectively suppressed ventricular arrhythmias in post-infarcted hearts by regulating miR-143-EGR1-NaV1.5/Kir2.1 axis, which provides novel therapeutic strategies for ischemic arrhythmias in clinics.

Hard Cr2O3 coatings on SS316L substrates prepared by reactive magnetron sputtering technique: a potential candidate for orthopedic implants.

316L stainless steel (SS) implants suffer from tribological and biocompatibility problems which limit their service lifetime. In order to improve the surface properties of 316L SS for orthopedic implant applications, hard chromium oxide coatings were applied on 316L SS substrates using a reactive magnetron sputtering technique. The morphological, structural, and phase compositional analyses were conducted on the deposited coatings by scanning electron microscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. The Rockwell-C indentation tests were performed on the coated substrates to qualitatively evaluate the adhesion of coatings on the steel substrates. The surface characteristics of coatings were measured by using an optical profilometer. The mechanical properties of coatings were reported by measuring the Hardness and Young's modulus. The corrosion resistance of coated and uncoated SS substrates was compared using potentiodynamic polarization tests. An inductively coupled plasma optical emission spectrometry (ICP-OES) was employed to analyze the biocompatibility of the samples by measuring the amount of toxic Cr ions released after the immersion test. The results show that the coatings are adherent and composed of a single Cr2O3 phase with a hardness of 25 to 29 GPa. The corrosion resistance of the SS has been improved by applying a chromium oxide coating. The coated SS samples have also demonstrated better wear resistance and lower friction coefficient compared to bare SS samples under a reciprocating sliding condition in saline solution. The biocompatibility of the SS has been enhanced by the Cr2O3 coating as much less Cr ions were released after immersion tests. These results indicate that the hard Cr2O3 coatings can be considered as a candidate for extending the lifetime of SS implants.

Desmin Correlated with Cx43 May Facilitate Intercellular Electrical Coupling during Chronic Heart Failure.

Desmin is one of five major intermediate filament proteins in cardiomyocytes. Desmin contributes to the maintenance of healthy muscle. The desmin content in cardiomyocytes directly affects the long-term prognosis of patients with heart failure, and lack of desmin leads to myocyte contractile dysfunction. However, the mechanism is elusive. In this study, we measured desmin expression using western blotting and qPCR in the failed hearts of human patients and rats. Our results showed that desmin content was reduced at the protein level in failed hearts and isolated cardiomyocytes. The association of desmin and the gap junction proteins connexin 43 (Cx43) and zonula occludens-1 (ZO-1) was also investigated. Immunoprecipitation assay showed that desmin was associated with Cx43 in cardiomyocytes. To compare the electrical integration of skeletal myoblasts in cocultures with cardiac myocytes, familial amyloid polyneuropathy (FAP) activation rate was found in 33% desmin overexpressing skeletal myoblasts. Desmin not only affected Cx43 and ZO-1 expression but also facilitated the complex of Cx43 and ZO-1 in skeletal myoblasts, which enhanced cell-to-cell electrical coupling of skeletal myoblasts with cardiac myocytes. Desmin has potential as a novel therapeutic target for heart failure. Preservation of desmin may attenuate heart failure.

Fibroblast Growth Factor 21 Ameliorates NaV1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes.

Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7-10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7-10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (I Na) and inward rectifier potassium (I k1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.

Autofluorescence-free in vivo multicolor imaging using upconversion fluoride nanocrystals.

Non-invasive fluorescence imaging is an important technique in biology. However, detection of traditional biomarker emissions is accompanied by a high background signal. In this study we examined whether upconversion sodium yttrium fluoride (NaYF(4)) nanocrystals were suitable for autofluorescence-free multicolor fluorescence imaging in a living animal. Tissue autofluorescence was induced with a 405 nm light source, then rats were subjected to injection of fluorescein isothiocyanate (FITC), cadmium selenide/zinc sulfide (CdSe/ZnS) quantum dots (QDs), or NaYF(4):ytterbium/thulium (Yb(3+)/Tm(3+)), NaYF(4):Yb(3+)/holmium (Ho(3+)), and NaYF(4):Yb(3+)/Ho(3+)/cerium (Ce(3+)) nanocrystals. Imaging with NaYF(4) nanocrystals (974 nm laser) completely removed the high tissue autofluorescence, in marked contrast to imaging with FITC and QDs (405 nm light). Optical imaging experiments demonstrated that multiple biological targets and organs could be imaged at the same time using multicolor NaYF(4) upconversion nanocrystals under a single excitation wavelength (974 nm). These data demonstrated the proof-of-principle that autofluorescence-free multicolor imaging using near-infrared to visible upconversion of NaYF(4) nanocrystals excited by laser can be performed in a living animal.

Valsartan alleviates atherosclerotic lesions in pulmonary arteries of rabbits via an endothelium-dependent mechanism.

OBJECTIVE: Angiotensin II plays an important role in the pathogenesis of atherosclerosis. This study was designed to examine the effect of valsartan, an angiotensin receptor blocker, on atherosclerotic lesions in pulmonary arteries of rabbits with atherosclerosis induced by a high-cholesterol (HC) diet. METHODS: Male New Zealand rabbits were randomly divided into four groups: control, HC without valsartan, HC with 3 mg/kg/d valsartan, and HC with 10 mg/kg/d valsartan. Following 12 weeks of treatment, serum lipid profiles were determined. Pulmonary arteries were harvested and stained with Sudan IV for evaluation of atherosclerotic lesions. The middle lobes of the rabbit lungs were isolated, embedded in paraffin, and sectioned and stained with haematoxylin and eosin. Nitric oxide (NO) and endothelin-1 (ET-1) levels were determined in pulmonary arteries by nitrate reductase assay and radioimmunoassay, respectively. RESULTS: HC feeding altered serum lipid levels and induced atherosclerotic lesions in pulmonary arteries. Although 12 weeks of valsartan treatment failed to alter serum lipid levels, it significantly ameliorated HC-induced atherosclerotic lesions. Lesion areas, inflammatory cell infiltration, and occlusions of small arteries of lungs were reduced. Moreover, the endothelium-derived NO levels in pulmonary arteries were increased by valsartan treatment (10 mg/kg/d) compared to levels in the HC group. ET-1 levels were decreased by valsartan treatment compared to levels in the HC group. NO and ET-1 levels were not altered by valsartan at 3 mg/kg/d. CONCLUSION: Our data demonstrates that HC diet-induced atherosclerotic lesions in rabbit pulmonary arteries can be ameliorated by treatment with valsartan, possibly through a NO and ET-1-dependent mechanism.

Diamond Deposition on Iron and Steel Substrates: A Review.

This article presents an overview of the research in chemical vapor deposition (CVD) diamond films on steel substrates. Since the steels are the most commonly used and cost-effective structural materials in modern industry, CVD coating diamond films on steel substrates are extremely important, combining the unique surface properties of diamond with the superior toughness and strength of the core steel substrates, and will open up many new applications in the industry. However, CVD diamond deposition on steel substrates continues to be a persistent problem. We go through the most relevant results of the last two and a half decades, including recent advances in our group. This review discusses the essential reason of the thick catalytic graphite interlayer formed on steel substrates before diamond deposition. The high carbon diffusion in iron would induce severe internal carburization, and then voluminous graphite precipitated from the substrate. In order to hinder the catalytic graphite formation, various methods have been applied for the adherent diamond film deposition, such as pre-imposed various interlayers or multi-interlayers, special controls of the deposition process, the approaches of substrate alloying and so on. We found that adherent diamond films can be directly deposited on Al alloying steel substrates, and then the role of Al alloying element was examined. That is a thin dense amorphous alumina sublayer in situ formed on the alloying substrate, which played a critical role in preventing the formation of graphite phase and consequently enhancing diamond growth and adhesion. The mechanism of Al alloying suggests that the way used to improve hot corrosion resistance is also applicable. Then, some of the hot corrosion resistance methods, such as aluminizing, siliconizing, and so on, which have been used by some researchers examining CVD diamond films on steel substrates, are reviewed. Another way is to prepare diamond-like carbon (DLC) films on steel substrates at low temperature, and then the precipitated graphite from the internal carburization can be effectively avoided. In addition, based on some new findings, the understanding of the diamond nucleation and metastable growth is discussed.

The role of desmin alterations in mechanical electrical feedback in heart failure.

AIM: Mechanoelectric feedback (MEF) was related to malignant arrhythmias in heart failure (HF). Desmin is a cytoskeleton protein and could be involved in MEF as a mechanoelectrical transducer. In this study, we will discuss the role of desmin alterations in mechanical electrical feedback in heart failure and its mechanisms. METHODS: We used both an in vivo rat model and an in vitro cardiomyocyte model to address this issue. For the in vivo experiments, we establish a sham group, an HF group, streptomycin (SM) group, and an MDL-28170 group. The occurrence of ventricular arrhythmias (VA) was recorded in each group. For the in vitro cardiomyocyte model, we established an NC group, a si-desmin group, and a si-desmin + NBD IKK group. The expression of desmin, IKKß, p-IKKß, IKBα, p-NF-κB, and SERCA2 were detected in both in vivo and in vitro experiments. The content of Ca2+ in cytoplasm and sarcoplasmic were detected by confocal imaging in vitro experiments. RESULTS: An increased number of VAs were found in the HF group. SM and MDL-28170 can reduce desmin breakdown and the number of VAs in heart failure. The knockdown of desmin in the cardiomyocyte can activate the NF-κB pathway, decrease the level of SERCA2, and result in abnormal distribution of Ca2+. While treatment with NF-κB inhibitor can elevate the level of SERCA2 and alleviate the abnormal distribution of Ca2+. SIGNIFICANCE: Overall, desmin may participate in MEF through the NF-κB pathway. This study provides a potential therapeutic target for VA in HF.

Erratum: Zhang, C. et al., The Effect of Substrate Biasing during DC Magnetron Sputtering on the Quality of VO2 Thin Films and Their Insulator-Metal Transition Behavior. Materials 2019, 12, 2160.

The authors would like to correct a typographical error in their paper [...].

The Effect of Substrate Biasing during DC Magnetron Sputtering on the Quality of VO2 Thin Films and Their Insulator-Metal Transition Behavior.

In this work, VO2 thin films were deposited on Si wafers (onto (100) surface) by DC magnetron sputtering under different cathode bias voltages. The effects of substrate biasing on the structural and optical properties were investigated. The results show that the metal-insulator transition (MIT) temperature of VO2 thin films can be increased up to 14 K by applying a cathode bias voltage, compared to deposition conditions without any bias. The decrease in the transition efficiency and increase in the transition temperature are attributed to the enlarged grain size, increased defects, and the residual stress in the VO2 thin films induced by biasing. The optical transmittance measurements for different thickness films indicate an attenuation coefficient of 3.1 × 107 m-1 at 2000 nm or an extinction coefficient of 4.9 in the metal phase. The optical transmittance vs wavelength characteristics point to an indirect bandgap of 0.6 ± 0.5 eV and significant scattering in the bulk and/or at the interface.

MiR-130a inhibition protects rat cardiac myocytes from hypoxia-triggered apoptosis by targeting Smad4.

BACKGROUND: Cardiomyocyte death facilitates the pathological process underlying ischaemic heart diseases, such as myocardial infarction. Emerging evidence suggests that microRNAs play a critical role in the pathological process underlying myocardial infarction by regulating cardiomyocyte apoptosis. However, the relevance of miR-130a in regulating cardiomyocyte apoptosis and the underlying mechanism are still uncertain. AIM: We sought to explore the regulatory effect of miR-130a on hypoxic cardiomyocyte apoptosis. METHODS: The expression of miR-130a was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell survival was determined by the MTT assay. The lactate dehydrogenase (LDH) assay was performed to deter-mine the severity of hypoxia-induced cell injury. Apoptosis was assessed via caspase-3 analysis. Protein expression level was determined by Western blotting. The genes targeted by miR-130a were predicted using bioinformatics and were validated via the dual-luciferase reporter assay system. RESULTS: We found that miR-130a expression was greatly increased in hypoxic cardiac myocytes, and that the downregulation of miR-130a effectively shielded cardiac myocytes from hypoxia-triggered apoptosis. In bioinformatic analysis the Smad4 gene was predicted to be the target of miR-130a. This finding was validated through the Western blot assay, dual-luciferase reporter gene assay, and qRT-PCR. MiR-130a inhibition significantly promoted the activation of Smad4 in hypoxic cardiomyocytes. Inter-estingly, knockdown of Smad4 markedly reversed the protective effects induced by miR-130a inhibition. Moreover, we found that the inhibition of miR-130a promoted the activation of transforming growth factor-b1 signalling. Blocking of Smad4 signal-ling significantly abrogated the protective effects of miR-130a inhibition. CONCLUSIONS: The findings indicate that inhibition of miR-130a, which targets the Smad4 gene, shields cardiac myocytes from hypoxic apoptosis. This study offers a novel perspective on the molecular basis of hypoxia-induced cardiomyocyte apoptosis and suggests a possible drug target for the treatment of myocardial infarction.

Histone demethylase JARID1B regulates proliferation and migration of pulmonary arterial smooth muscle cells in mice with chronic hypoxia-induced pulmonary hypertension via nuclear factor-kappa B (NFkB).

Chronic hypoxia-induced pulmonary hypertension (PH) is a disorder that is characterized by increased pulmonary arterial pressure resulting from lung diseases or shortage of oxygen in the body. Excess proliferation of pulmonary vascular cells such as pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of PH. Recent evidence indicates that, in addition to genetic predisposition and environmental factors, epigenetic mechanisms play a pivotal role in etiology of PH. In this study, we investigated the possible role played by jumonji AT-rich interactive domain 1B (JARID1B), a histone demethylase, in regulating the proliferation of vascular smooth muscle cells in chronic hypoxia-induced PH condition. Quantitative polymerase chain reaction analysis of samples from rats with PH showed an elevated expression of JARID1B in their PASMCs, positively correlating with increased nuclear factor-kappa B (NFkB) expression. Further functional studies in vitro indicated that overexpression of JARID1B increased the proliferation and migration of PASMCs, which were inhibited by depletion of NFkB. Genomewide transcriptional analysis revealed that the JARID1B regulated NFkB signaling pathway by directly binding to its promoter. We have also shown that JARID1B indirectly regulates the expression of vascular endothelial growth factor via NFkB signaling and hence may also play a crucial role in controlling PAECs, leading to changes in vascular architecture in PH. Our findings could lead to further studies on the role of JARID1B in PH etiology and therefore could lead to a potential therapeutic target for chronic hypoxia induced pulmonary hypertension.

[Correlation of hyponatremia with plasma renin activity, antidiuretic hormone and brain natriuretic peptide in chronic heart failure].

OBJECTIVE: To observe the changes of plasma renin activity, antidiuretic hormone and brain natriuretic peptide in chronic heart failure (CHF) and their correlation with hyponatremia. METHODS: Plasma levels of PRA, ADH, and BNP were measured by radioimmunology in 76 CHF patients. Forty-one out of 76 CHF patients with hyponatremia and 35 CHF patients without hyponatremia were identified by serum sodium. The rates of rehospitalization within 3 months were compared in two groups. RESULTS: Levels of plasma renin activity, ALD, and BNP in CHF patients with hyponatremia were notably higher than those in patients without hyponatremia classified by New York Heart Association (NYHA) grade II - IV: PRA [(2.7 +/- 1.0) ng.ml(-1).h(-1) vs. (1.8 +/- 0.7) ng.ml(-1).h(-1), (4.3 +/- 1.2) ng.ml(-1).h(-1) vs. (3.0 +/- 0.9) ng.ml(-1).h(-1), (5.6 +/- 1.3) ng.ml(-1).h(-1) vs. (3.5 +/- 1.1) ng.ml(-1).h(-1), respectively, P < 0.05], ADH [(59.7 +/- 17.4) ng/L vs. (48.6 +/- 15.3) ng/L, (68.4 +/- 17.6) ng/L vs. (56.3 +/- 19.2) ng/L, (75.3 +/- 20.0) ng/L vs. (51.4 +/- 16.2) ng/L, respectively, P < 0.05] and BNP [(276.4 +/- 75.2) ng/L vs. (185.3 +/- 55.3) ng/L, (380.1 +/- 113.6) ng/L vs. (258.5 +/- 62.1) ng/L, (564.0 +/- 125.2) ng/L vs. (405.3 +/- 102.9) ng/L, respectively, P < 0.05]. In the simple regression analyses, hyponatremia was negative correlated with PRA, ADH and BNP (r = -0.31, P < 0.05; r = -0.28, P < 0.05, r = -0.80, P < 0.01). The rate of rehospitalization within 3 months in hyponatremia group was higher than that in control group. CONCLUSIONS: There is relation of hyponatremia to the changes of plasma renin activity, antidiuretic hormone and brain natriuretic peptide in chronic heart failure. Hyponatremia may accelerate the excretion of plasma PRA, ADH and BNP in chronic heart failure. Neuroendocrine activation in patients of congestive heart failure with hyponatremia is higher than that of normal natremia group.

Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway.

Treatment with doxorubicin (DOX) is one of the major causes of chemotherapy-induced cardiotoxicity and is therefore, the principal limiting factor in the effectiveness of chemotherapy for cancer patients. DOX­induced heart failure is thought to result from endoplasmic reticulum (ER) stress and cardiomyocyte apoptosis. Resveratrol (RV), a polyphenol antioxidant found in red wine, has been shown to play a cardioprotective role. The aim of the present study was to examine the effects of RV on DOX­induced cardiotoxicity in H9c2 cells. We hypothesized that RV would protect H9c2 cells against DOX­induced ER stress and subsequent cell death through the activation of the Sirt1 pathway. Our results demonstrated that the decrease observed in the viability of the H9c2 cells following exposure to DOX was accompanied by a significant increase in the expression of the ER stress­related proteins, glucose­regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). However, we found that RV downregulated the expression of ER stress marker protein in the presence of DOX and restored the viability of the H9c2 cells. Exposure to RV or DOX alone only slightly increased the protein expression of Sirt1, whereas a significant increase in Sirt1 protein levels was observed in the cells treated with both RV and DOX. The Sirt1 inhibitor, nicotinamide (NIC), partially neutralized the effects of RV on the expression of Sirt1 in the DOX­treated cells and completely abolished the effects of RV on the expression of GRP78 and CHOP. The findings of our study suggest that RV protects H9c2 cells against DOX­induced ER stress through ER stabilization, and more specifically through the activation of the Sirt1 pathway, thereby leading to cardiac cell survival.

Detection and photodynamic therapy of inflamed atherosclerotic plaques in the carotid artery of rabbits.

Photodynamic therapy (PDT) has been applied in the treatment of artery restenosis following balloon injury. This study aimed to detect the accumulation of 5-aminolevulinic acid (ALA)-derived protoporphyrin IX (PpIX) in inflamed atherosclerotic plaque in rabbit model and evaluate the efficacy of PDT. The inflamed atherosclerotic plaque in the common carotid artery was produced by combination of balloon denudation injury and high cholesterol diet. After intravenous administration of ALA, the fluorescence of PpIX in plaque was detected. At the peak time, the correlation between the fluorescence intensity of PpIX and the macrophage infiltration extent in plaque was analyzed. Subsequently, PDT (635nm at 50J/cm(2)) on the atherosclerotic plaques (n=48) was performed and its effect was evaluated by histopathology and immunohistochemistry. The fluorescence intensity of PpIX in the plaque reached the peak 2h after injection and was 12 times stronger than that of adjacent normal vessel segment, and has a positive correlation with the macrophage content (r=0.794, P<0.001). Compared with the control group, the plaque area was reduced by 59% (P<0.001) at 4week after PDT, the plaque macrophage content decreased by 56% at 1week and 64% at 4week respectively, the smooth muscle cells (SMCs) was depleted by 24% at 1week (P<0.05) and collagen content increased by 44% at 4week (P<0.05). It should be pointed out that the SMC content increased by 18% after PDT at 4week compared with that at 1week (P<0.05). Our study demonstrated that the ALA-derived PpIX can be detected to reflect the macrophage content in the plaque. ALA mediated PDT could reduce macrophage content and inhibit plaque progression, indicating a promising approach to treat inflamed atherosclerotic plaques.

Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction.

To investigate the changes of inducible cAMP early repressor (ICER) and phosphodiesterase 3A in rats after myocardial infarction and to evaluate the beneficial effects of valsartan on cardiac function and ventricular remodeling. Rats were split into four groups: sham-operation group, pre-myocardial infarction group (valsartan administration 2 weeks before myocardial infarction), post-myocardial infarction group (valsartan administration after myocardial infarction) and myocardial infarction group (vehicle after myocardial infarction). Echocardiograph and hemodynamic data were measured and cardiocyte apoptosis was estimated by TUNEL staining. ICER, cAMP response element binding protein (CREB), phosphodiesterase 3A and Bcl-2 mRNA expression levels were assayed by real-time reverse transcriptase polymerase chain reaction and protein expression was measured using immunoblot analysis. ICER and CREB mRNA expression in the myocardial infarction group were higher and phosphodiesterase 3A and Bcl-2 mRNA expression were lower than the sham-operation group (Ps<0.01). Following the improvement of cardiac function and ventricular remodeling, ICER and CREB mRNA in pre- and post- myocardial-infarction groups were down-regulated, and phosphodiesterase 3A and Bcl-2 mRNA were up-regulated (P<0.05). The changes brought on by valsartan pre-myocardial infarction were stronger than post-myocardial infarction (P<0.05). These data suggest that there is a phosphodiesterase 3A-ICER positive-feedback loop leading to myocyte apoptosis and ongoing development of heart failure after myocardial infarction. Maintaining the function of phosphodiesterase 3A or reducing ICER may be an effective way to prevent myocardium apoptosis and heart dysfunction. Valsartan can ameliorate ventricular remodeling and heart failure by inhibiting the expression of ICER and increasing the expression of phosphodiesterase 3A.