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Phosphodiesterase type 3 (PDE3) inhibitors block the cAMP hydrolyzing activity of both PDE3 isoforms, PDE3A and PDE3B, which have distinct roles in the heart. Although PDE3 inhibitors improve cardiac function in heart disease patients, they also increase mortality. Nevertheless, PDE3 inhibitors can provide benefit to non-ischemic heart disease patients and are used extensively to treat heart failure in dogs. Since the isoform-dependence of the complex cardiac actions of PDE3 inhibition in diseased hearts remains unknown, we assessed the effects of PDE3 inhibitors as well as gene ablation of PDE3A or PDEB in mice following the induction of non-ischemic heart disease by pressure-overload with transverse-aortic constriction (TAC). As expected, after 6 weeks of TAC, mice exhibited left ventricular contractile dysfunction, dilation, hypertrophy and interstitial fibrosis, in association with increased macrophage numbers, activation of p38 MAPK and elevated PDE3 activity. Chronic PDE3 inhibition with milrinone (MIL), at doses that did not affect either cardiac contractility or arterial blood pressure, profoundly attenuated the adverse ventricular remodeling, reduced macrophage number and diminished p38-MAPK activation induced by TAC. Surprisingly, whole-body ablation of PDE3A, but not PDE3B, provided similar protection against TAC-induced adverse ventricular remodeling, and the addition of MIL to mice lacking PDE3A provided no further protection. Our results support the conclusion that PDE3A plays an important role in adverse cardiac remodeling induced by chronic pressure overload in mice, although the underlying biochemical mechanisms remain to be fully elucidated. The implications of this conclusion on the clinical use of PDE3 inhibitors are discussed. • PDE3 inhibition protects against ventricular remodeling due to pressure-overload. • This protection is associated with reduced p38 MAPK, calcineurin/NFAT activation. • PDE3A, not PDE3B, ablation protects against adverse effects of pressure-overload. • Cardiac PDE3 activity, PDE3A expression are increased with pressure overload. [ABSTRACT FROM AUTHOR]

Aims Endurance exercise is associated with an increased risk of atrial fibrillation (AF). We previously established that adverse atrial remodelling and AF susceptibility induced by intense exercise in mice require the mechanosensitive and pro-inflammatory cytokine tumour necrosis factor (TNF). The cellular and mechanistic basis for these TNF-mediated effects is unknown. Methods and results We studied the impact of Tnf excision, in either atrial cardiomyocytes or endothelial cells (using Cre -recombinase expression controlled by Nppa or Tie2 promoters, respectively), on the cardiac responses to six weeks of intense swim exercise training. TNF ablation, in either cell type, had no impact on the changes in heart rate, autonomic tone, or left ventricular structure and function induced by exercise training. Tnf excision in atrial cardiomyocytes did, however, prevent atrial hypertrophy, fibrosis, and macrophage infiltration as well as conduction slowing and increased AF susceptibility arising from exercise training. In contrast, endothelial-specific excision only reduced the training-induced atrial hypertrophy. Consistent with these cell-specific effects of Tnf excision, inducing TNF loss from atrial cardiomyocytes prevented activation of p38MAPKinase, a strain-dependent downstream mediator of TNF signalling, without affecting the atrial stretch as assessed by atrial pressures induced by exercise. Despite TNF's established role in innate immune responses and inflammation, neither acute nor chronic exercise training caused measurable NLRP3 inflammasome activation. Conclusions Our findings demonstrate that adverse atrial remodelling and AF vulnerability induced by intense exercise require TNF in atrial cardiomyocytes whereas the impact of endothelial-derived TNF is limited to hypertrophy modulation. The implications of the cell autonomous effects of TNF and crosstalk between cells in the atria are discussed. [ABSTRACT FROM AUTHOR]

Activating transcription factor 1 (ATF1) may be involved in essential hypertension (EH) by induction of NADPH oxidase 1 (NOX1) and radical oxygen species (ROSs) production. Abnormal expression of ATF1 was found in EH in previous microarray analysis. Here we tested whether a single nucleotide polymorphism (SNP) located in the 3′-untranslated region (3′UTR) of ATF1 was associated with EH susceptibility by affecting microRNA (miRNA) binding. In silico analysis indicated that rs11169571 (T > C) was a candidate SNP to modulate miRNA: ATF1 mRNA complex, with the greatest changed energy for hsa-miR-1283, and the luciferase reporter analysis showed that miR-1283 inhibited the activity of the reporter vector carrying –T allele, but not the –C allele. In addition, inhibition of miR-1283 in HA-VSMCs enhanced the expression of ATF1 mRNA as well as the ROS levels. Further case-control study showed that rs11169571 was significantly associated with increased risk of EH. Finally, we observed an increased ATF1 protein level in peripheral blood of EH patients with CC carriers compared to TT carriers of rs11169571, with an intermediate ATF1 level in TC carriers. These results suggested that rs11169571 of ATF1 gene may be associated with EH, and the SNP-modified posttranscriptional gene regulation by miRNAs could be a potentially pathogenetic mechanism of EH. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum aminopeptidase 1 (ERAP1) may be involved in blood pressure regulation by inactivation of angiotensin II and generation of bradykinin. Our previous study with cDNA microarray indicated that the expression of ERAP1 is down-regulated in essential hypertension (EH) patients. Since the 3′untranslated region (3′UTR) is known to play an important role in the post-transcriptional regulation by influencing the stability and translation process of mRNA, the present study aims to identify single nucleotide polymorphisms (SNPs) in the 3′UTR of ERAP1 gene in a case–control study among the Northeastern Han Chinese through PCR-sequencing, and analyze the association with EH. Our results further verified the lower expression level of ERAP1 in the peripheral blood cells in patients with EH (917.12 ± 517.57 vs. 1506.59 ± 1214.09 pg/mL, P = 0.011). Four SNPs, 3′UTR-761G>A, 3′UTR-787C>T, 3′UTR-1008A>C and 3′UTR-1055A>G, were identified in the 3′UTR of ERAP1 . 3′UTR-1008A>C and 3′UTR-1055A>G were in almost complete linkage disequilibrium. Association analysis showed that the genotypic and allelic frequencies of 3′UTR-1008A>C and 3′UTR-1055A>G were significantly different between EH and the control groups. Logistic regression and haplotypic analysis indicated that alleles of E20-1037C and E20-1084G as well as haplotype of C-G were the risk factors of EH (P < 0.05). Subgroup analysis performed by age suggested that the frequencies of genotype and allele of 3′UTR-1008A>C and 3′UTR-1055A>G as well as the haplotypes C-G and A-A were significantly different between EH and the control in the younger group (< 50), but not in the older group (≥ 50). Younger population with the 3′UTR-1008CC and/or 3′UTR-1055GG genotypes also tended to have higher blood pressure, especially the diastolic blood pressure. In conclusion, the 3′UTR-1008A>C and 3′UTR-1055A>G polymorphisms of ERAP1 gene were associated with EH, especially in the younger population, and the haplotype C-G could be the independent marker of EH. [ABSTRACT FROM AUTHOR]

Intense endurance exercise is linked to atrial fibrillation (AF). We established previously that interventions that simultaneously interfere with TNFα signaling, mediated via both the enzymatically liberated soluble and membrane-bound forms of TNFα, prevent atrial remodeling and AF vulnerability in exercised mice. To investigate which signaling modality underlies this protection, we treated exercised mice with XPRO®1595, a selective dominant-negative inhibitor of solTNFα. In male CD1 mice, 6 weeks of intense swim exercise induced reductions in heart rate, increased cardiac vagal tone, left ventricular (LV) dilation and enhanced LV function. By contrast, exercise induced hypertrophy, fibrosis, and increased inflammatory cell infiltrates in atria, and these changes were associated with increased AF susceptibility in isolated atria as well as mice, with and without parasympathetic nerve blockade. Although XPRO treatment had no effect on the beneficial physiological changes induced by exercise, it protected against adverse atrial changes as well as AF susceptibility. Our results establish that soluble TNFα is required for exercise-induced increases in AF vulnerability, which is linked to fibrosis, inflammation, and enlargement of the atria, but largely independent of changes in vagal tone. • Intense endurance exercise is associated with atrial fibrillation (AF) in mice. • Exercise induced atrial hypertrophy, fibrosis, and inflammatory cell infiltrates. • Inhibiting soluble TNFα prevented adverse atrial remodeling and AF vulnerability. • HR reductions and physiological remodeling of the ventricles were unaffected. • Soluble TNFα is required for increased AF vulnerability induced by intense exercise. [ABSTRACT FROM AUTHOR]

Background: Heart failure is a complex end stage of various cardiovascular diseases with a poor prognosis, and the mechanisms for development and progression of heart failure have always been a hot point. However, the molecular mechanisms underlying the post transcriptional regulation of heart failure have not been fully elucidated. Current data suggest that microRNAs (miRNAs) are involved in the pathogenesis of heart failure and could serve as a new biomarker, but the precise regulatory mechanisms are still unclear. Methods: The differential miRNA profile in a rat model of post-infarction heart failure was determined using high throughout sequencing and analyzed through bioinformatics approaches. The results were validated using qRT-PCR for 8 selected miRNAs. Then the expression patterns of 4 miRNAs were analyzed in different periods after myocardial infarction. Finally, gain- and loss-of-function experiments of rno-miR-122-5p and rno-miR-184 were analyzed in H2O2 treated H9c2 cells. Results: In the heart failure sample, 78 miRNAs were significantly upregulated and 28 were downregulated compared to the controls. GO and KEGG pathway analysis further indicated the likely roles of these miRNAs in heart failure. Time-course analysis revealed different expression patterns of 4 miRNAs: rno-miR-122-5p, rno-miR-199a-5p, rno-miR-184 and rno-miR-208a-3p. Additionally, rno-miR-122-5p and rno-miR-184 were proved to promote apoptosis in vitro. Conclusions: Differential profile and expression patterns of miRNAs in the rats model of post-infarction heart failure were found, and the pro-apoptotic roles of rno-miR-122-5p and rno-miR-184 were revealed. These findings may provide a novel way that may assist in heart failure diagnosis and treatment. [ABSTRACT FROM AUTHOR]