Predictive value of serum HIF-1α and VEGF for arrhythmia in acute coronary syndrome patients.

Percutaneous coronary intervention (PCI) has been widely used in the alleviation of myocardial ischemia in patients with acute coronary syndrome (ACS). However, the incidence of reperfusion arrhythmia (RA) after PCI is high, which seriously affects the prognosis of ACS patients. Therefore, this study aimed to study the predictive value of serum HIF-1α and VEGF levels before PCI for RA in ACS patients post PCI. A total of 200 ACS patients who underwent PCI were selected and divided into those with RA after PCI (RA, n = 93) and those without RA after PCI (non-RA, n = 107) according to Lown grade. Spearman correlation analysis was applied for the relationship between serum hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) levels and Lown grade. Patients with RA after PCI tended to have higher levels of creatine kinase muscle and brain isoenzyme (CK-MB), serum HIF-1α and VEGF before surgery. Low left ventricular ejection fraction (LVEF), high CK-MB, high serum VEGF and HIF-1α were risk factors for RA in ACS patients within 24 h after PCI. Receiver operating characteristic (ROC) analysis revealed that serum HIF-1α and VEGF levels could predict RA in ACS patients after PCI, and the combined detection could increase the sensitivity of single HIF-1α detection and the specificity of single VEGF detection. Lown grade was positively correlated with the serum HIF-1α and VEGF concentrations. In conclusion, serum HIF-1α and VEGF levels before PCI are risk factors for the occurrence of RA in ACS patients after PCI, and have certain predictive values for the occurrence of RA in ACS patients after PCI.

Super-resolution of brain tumor MRI images based on deep learning.

INTRODUCTION: To explore and evaluate the performance of MRI-based brain tumor super-resolution generative adversarial network (MRBT-SR-GAN) for improving the MRI image resolution in brain tumors. METHODS: A total of 237 patients from December 2018 and April 2020 with T2-fluid attenuated inversion recovery (FLAIR) MR images (one image per patient) were included in the present research to form the super-resolution MR dataset. The MRBT-SR-GAN was modified from the enhanced super-resolution generative adversarial networks (ESRGAN) architecture, which could effectively recover high-resolution MRI images while retaining the quality of the images. The T2-FLAIR images from the brain tumor segmentation (BRATS) dataset were used to evaluate the performance of MRBT-SR-GAN contributed to the BRATS task. RESULTS: The super-resolution T2-FLAIR images yielded a 0.062 dice ratio improvement from 0.724 to 0.786 compared with the original low-resolution T2-FLAIR images, indicating the robustness of MRBT-SR-GAN in providing more substantial supervision for intensity consistency and texture recovery of the MRI images. The MRBT-SR-GAN was also modified and generalized to perform slice interpolation and other tasks. CONCLUSIONS: MRBT-SR-GAN exhibited great potential in the early detection and accurate evaluation of the recurrence and prognosis of brain tumors, which could be employed in brain tumor surgery planning and navigation. In addition, this technique renders precise radiotherapy possible. The design paradigm of the MRBT-SR-GAN neural network may be applied for medical image super-resolution in other diseases with different modalities as well.

Value of PTEN and Echocardiography in Predicting the Efficacy of Trimetazidine Combined with Metoprolol in the Treatment of Heart Failure.

OBJECTIVE: To investigate the predictive value of PTEN and echocardiography in the treatment of heart failure with trimetazidine combined with metoprolol. METHODS: A total of 100 patients with coronary heart disease and HF who admitted to our hospital from August 2018 to August 2020 were enrolled into research. All patients received routine treatment according to the guidelines and were treated with trimetazidine and metoprolol for a total course of 6 months. Echocardiographic parameters and PTEN levels were measured at baseline and after treatment. The patients were divided into groups according to the quartile of basic PTEN level, and the total effective rates were compared. The echocardiographic parameters of patients with different prognosis were analyzed. Bivariate correlation analysis was used to evaluate the correlation between PTEN, echocardiography and treatment effect. RESULTS: Compared with that before treatment, the level of PTEN increased significantly after treatment (P < 0.01). According to the quartile of basic PTEN level, the total effective rate of patients with different levels of basic PTEN was was statistically different (P < 0.01). There was a linear correlation between the level of basic PTEN and the treatment effect, and the total effective rate of patients with high level of basic PTEN was higher than that of patients with low level of PTEN. Compared with before treatment, LVEF, SV, E/A and lvfs increased significantly after treatment (P < 0.01). There was a correlation between the basic echocardiographic parameters and the treatment effect of patients. The basic echocardiographic parameters of patients with poor prognosis were worse than those with good prognosis. PTEN expression in patients' serum was only positively correlated with E/A, but not with LVFE, SV and LVFS (P < 0.01). CONCLUSION: PTEN and echocardiographic parameters serve as a good method to evaluate the short-term therapeutic effect of trimetazidine combined with metoprolol in patients with heart failure.

PTEN inhibitor improves vascular remodeling and cardiac function after myocardial infarction through PI3k/Akt/VEGF signaling pathway.

BACKGROUND: Myocardial infarction (MI) is the leading cause of death from cardiovascular disease (CVD). Currently, the efficacy for MI treatment remains unsatisfactory. Therefore, it is urgent to develop a novel therapeutic strategy. METHODS: Left anterior descending arteries (LAD) of mice were ligated to induce MI. Another set of mice were intravenously injected with PTEN inhibitor BPV (1 mg/kg) 1 h after LAD ligation and continued to receive BPV injection daily for the following 6 days. Mice were performed echocardiography 14 days after surgery. RESULTS: Mice in MI group displayed an increased expression of PTEN with impaired cardiac function, enhanced cardiomyocyte apoptosis and decreased angiogenesis. BPV treatment significantly improved cardiac function, with reduced cardiomyocyte apoptosis, promoted angiogenesis, and activated PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway. CONCLUSION: PTEN inhibitor BPV could effectively prevent myocardial infarction in mice, highlighting its potential as a candidate therapeutic drug.

Association between Dietary Vitamin A and HPV Infection in American Women: Data from NHANES 2003-2016.

OBJECTIVE: Evidence regarding the relationship between vitamin A and HPV infection was limited. Therefore, this study is designed to investigate whether vitamin A was independently related to HPV infection in 13412 American women from NHANES for seven cycles. METHODS: The present study is a cross-sectional study. A total of 13412 eligible participants who had available HPV tests and vitamin A intake data were registered in the NHANE database from 2003 to 2016. The targeted independent variable and the dependent variable were vitamin A measured at baseline and HPV infection, respectively. We analyzed the association between dietary vitamin A intake and the prevalence of HPV infection. Besides, GAM and smooth curve fittings were used to address the nonlinear relationship between vitamin A and HPV infection to determine the effect of HPV infection. RESULTS: The result of fully adjusted binary logistic regression showed vitamin A was not associated with the risk of HPV infection after adjusting confounders (odds ratio = 0.97, 95% confidence interval: 0.97-1.02). A nonlinear relationship was detected between vitamin A and HPV infection, whose inflection point was 10.5 of log2 vitamin A (by the recursive algorithm). One unit increase of log2 vitamin A is associated with the 10% reduced risk of HPV infection when dietary vitamin A is < 1448.155mcg. Conversely, when the dietary vitamin A intake is ≧1448.155 mcg, for each additional log2 of vitamin A, the risk of HPV infection increased by 70%. CONCLUSIONS: We found that dietary vitamin A was quite different from the trend of HPV infection in different confidence intervals. The results suggested that an appropriate amount (95% CI: 0.9-1.0, <10.5 of log2 transformer, i.e., 1448.155 mcg) of dietary vitamin A may be beneficial to prevent HPV infection. However, excessive intake of dietary vitamin A (95% CI: 1.1-2.8, ≧10.5 of log2 transformer, i.e., 1448.155 mcg) may increase the risk of HPV infection.

The benefits of higher LMR for early threatened abortion: A retrospective cohort study.

PROBLEM: To investigate the relation of inflammation-related parameters and pregnancy outcome in women with the early threatened abortion. METHOD OF STUDY: 630 women with early threatened abortion were divided into two groups based on the pregnancy outcome. All of them had the blood routine examination before treating. The differences between two groups were analyzed by the Chi-squared test, Student T test, Mann-Whitney U test, Binary Logistic Regression, Marginal Structural Model and Threshold effect analysis. RESULTS: We found that there is no significant difference in the pregnancy outcome for NLR (OR:0.92, CI95%:0.72, 1.17) and PLR (OR:1.00, CI%:0.99, 1.01). However, a difference had a statistical significance in the pregnancy outcome when LMR less than 2.19 (OR:0.39, CI95%:0.19,0.82). CONCLUSIONS: This study suggested that higher LMR was related to the lower risk of miscarriage in the women with early threatened abortion in a way.

Inhibition of MicroRNA-206 Ameliorates Ischemia-Reperfusion Arrhythmia in a Mouse Model by Targeting Connexin43.

Reperfusion arrhythmias (RA) are an important cause of sudden cardiac death and is closely associated with gap junction protein in the heart, connexin 43 (Cx43). This study is aimed at elucidating the molecular association between microRNA-206 (miR-206) and Cx43 in ischemia-reperfusion arrhythmia using experimental animal model. Our results showed that miR-206 inhibitor alleviated ischemia-reperfusion-induced arrhythmias, indicated by the lower extent of changes in heart rate (HR), PR interval, rate pressure product (RPP), and mean arterial pressure (MAP). miR-206 inhibitor also downregulated the serum creatine kinase isoenzyme (CKMB) and cardiac troponin I (cTnI) levels in mice under myocardial ischemia-reperfusion (IR) process. The knockdown of Cx43 inversed the protective effects of miR-206 inhibitor on cardiac arrhythmias. These results supported that inhibition of miR-206 ameliorates ischemia-reperfusion arrhythmia by targeting Cx43, and this miR-206/Cx43 axis could serve as a potential target for the management of ischemic-perfusion arrhythmia.

Involvement of miR-200b-PKCα signalling in pulmonary hypertension in cor pulmonale model.

The right ventricle (RV) enlargement and pulmonary fibrosis are involved in cor pulmonale. The role of miR-200b in cor pulmonale is less well understood. This study was designed to evaluate the regulatory roles of miR-200b in cor pulmonale. Cor pulmonary mouse model was built via monocrotaline injection of monocrotaline (MCT). The expression of miR-200b in the lungs, RV and left ventricle (LV) are using real-time polymerase chain reaction. The transthoracic echocardiography was employed to determine the effects of miR-200b mimics and Gö6976 injection on MCT mice. The protein levels of protein kinase C α (PKCα), collagen, and fibronectin in the lung, RV, and LV in the mice with and without miR-200b mimics and Gö6976 injection were evaluated using western blot. The expression of miR-200b decreased in MCT mice, while there was no difference in LV. Both the miR-200b mimics and Gö6976 injection reversed the muscularization in the pulmonary artery, reversed RV hypertrophy, reduced RV systolic pressure, wall thickness and pulmonary fibrosis. The injection of miR-200b can reduce the PKCα expression in the lung, RV, and LV. This study confirmed the down-regulation of miR-200b in cor pulmonale. The reverse effects of miR-200b in the present study may provide a potential tool for cor pulmonary treatment.

Differential contribution of the two waves of cardiac progenitors and their derivatives to aorta and pulmonary artery.

During mouse development, part of the cells derived from the second heart field (SHF) progenitors contributes to the elongation and enlargement of the outflow tract (OFT) that subsequently septates into the trunks of aorta (Ao) and pulmonary artery (PA). Thus, the cardiac progenitor-originated cells are distributed to both Ao and PA. Here, we investigated that how these cells are assigned to the two great arteries during OFT septation through lineage tracing technology. By use of the inducible Mef2c-AHF-CreERT2; Rosa26-mTmG reporter system, two waves of SHF progenitors and their derivatives were identified, and they made differential contribution to the Ao and PA, respectively. While the early wave of cells (at E7.5) was preferentially destined to the Ao, the second wave of cells (from E8.5 till E11.5) made its favorite path to the PA. In addition, we unveiled PDK1 as a critical regulator of the second wave of cells as deletion of Pdk1 resulted in poorly developed PA leading to pulmonary stenosis. Thus, this study provides insights into the understanding of the pre-determined cell fate of the cardiac progenitor-derived cells with preferential contribution to the Ao and PA, as well as of the pathogenesis of pulmonary stenosis.

MicroRNA-206 Downregulates Connexin43 in Cardiomyocytes to Induce Cardiac Arrhythmias in a Transgenic Mouse Model.

BACKGROUND: MicroRNAs (miRNAs) are critical modulators of various physiological and pathological processes, but their role in cardiac arrhythmias remains yet to be completely understood. Connexin43 (Cx43) is an important cardiac gap junction protein and a potential target of miR-206, and downregulation of Cx43 induces ventricular tachyarrhythmias. METHODS: We investigated the effects of miR-206 overexpression on the adult mouse heart and in cardiac arrhythmias. Luciferase activity assay was employed to validate Cx43 as a direct target of miR-206. Expression of Cx43 was measured in cardiac muscle cell line HL-1 securely expressing miR-206. An inducible miR-206 overexpression mouse model was established to evaluate the in vivo effect of miR-206 on Cx43 expression and cardiac rhythm. RESULTS: MiR-206 directly recognised 3'-untranslated region of Cx43 mRNA to inhibit its expression in HL-1 cells. Induction of miR-206 in the adult mouse heart suppressed Cx43 expression, particularly in the atria and ventricle. Importantly, miR-206 overexpression also induced abnormal heart-rate and PR interval, and shortened life-span in the experimental mice. CONCLUSIONS: In cardiomyocytes, miR-206 is a upstream regulator of Cx43, and its overexpression downregulates Cx43 to induce abnormal heart-rate and PR interval.

High serum YKL-40 level positively correlates with coronary artery disease.

AIM: We investigated the predictive value of chitinase-like protein YKL-40 in coronary artery disease (CAD). PATIENTS: Serum YKL-40 levels in 116 CAD patients and 82 healthy controls were analyzed. Severity of CAD was evaluated using Gensini scores. Spearman's correlation was used to evaluate the correlation between Gensini scores and YKL-40 levels. The predictive value of YKL-40 was determined by receivers operating characteristic curve analysis. RESULTS: Serum YKL-40 levels were significantly elevated in CAD group as compared with control group. A positive correlation was found between the serum YKL-40 level and Gensini score. The optimum cut-off value of YKL-40 concentration was 127.7 ng/ml for distinguishing CAD patients from healthy controls with a 75.9% sensitivity and 57.3% specificity. CONCLUSION: A positive correlation exists between YKL-40 levels and CAD, and YKL-40 might be a useful adjunct in the diagnosis of CAD.

Resveratrol promotes differentiation of mouse embryonic stem cells to cardiomyocytes.

AIM: Embryonic stem cells (ESCs) are capable to differentiate into cardiomyocytes, with the potential to treat cardiovascular diseases. However, directed differentiation is still a challenge faced by scientists. As a natural substance in grapes, resveratrol (RV) is important for cardiovascular protection. The studies of RV and its effects on ESC differentiation have potential clinical applications. METHODS: Using mouse embryonic stem cells (mESCs), we investigated the effects of different concentrations of RV (5, 10, 20, 50, and 100 µmol/L) exposure on mESCs viability, expression levels of cardiac marker genes in embryoid bodies (EBs) derived from mESCs, expression levels of maturity indicative cardiac markers in cardiomyocytes derived from mESCs, and the beating properties of EBs. RESULTS: About 10 µmol/L of RV showed no toxicity on cell viability and was the optimal concentration to promote mESC differentiation, induce mESC differentiation to cardiomyocytes, and gain the beating properties of EBs. CONCLUSION: RV can successfully direct the differentiation of mESCs into cardiomyocytes, shedding light on its future applications to treat cardiovascular diseases.

Effects of C-Reactive Protein on the Cardiac Differentiation of Mouse Embryonic Stem Cells.

A major challenge in stem cell therapy for cardiac repair is how to obtain normally functioning stem cell-derived cardiomyocytes. We aim to address the effects of C-reactive protein (CRP) on the cardiac differentiation of embryonic stem (ES) cells. Immunostaining, Western blotting and electrophysiology were employed. A hundred fifty milligran/liters CRP significantly reduced the percentage of cardiomyocytes differentiated from mouse ES cells, while it may also promote sarcomere development compared to 30 mg/L CRP treatment. Further examination of the action potential (AP) in individual ES cell-derived cardiomyocytes showed that there exist three types of cardiomyocytes: artial-like (A-like), ventricular-like (V-like), and pacemaker-like (P-like). A hundred fifty milligran/liters CRP treatment decreased the P-like cardiomyocytes, whereas it increased the A-like. Such inhibitory effect and alteration were not significant at 30 mg/L CRP treatment. Moreover, 150 mg/L CRP significantly increased the APD90 (90% of duration of AP) and decreased the spontaneous firing rate of AP in P-like cells, while had little effect on other electrophysiological characteristics, including APA (AP amplitude) and MDP (maximum diastolic potential). This study revealed the effect of CRP on the cardiac differentiation of ES cells. It provides an in vitro pathological model and may be of importance to the future work of ES cell-based therapy in clinical applications and in vivo pathological studies.

MiR-214 regulates the pathogenesis of patients with coronary artery disease by targeting VEGF.

Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. We aimed to investigate the correlation between the levels of circulating miR-214 and the expression of vascular endothelial growth factor (VEGF) in the pathogenesis of coronary heart disease patients to further explore the mechanism involved in the vasculogenesis. Three different cohorts, including 13 acute myocardial infarction patients, 176 angina pectoris patients, and 127 control subjects, were enrolled to investigate the expression levels of circulating miR-214 in patients with myocardial ischemia and also the relationship between plasma miR-214 and severity of coronary stenosis. Plasma miR-214 levels of participants were examined by real-time quantitative PCR. Simultaneously, plasma cardiac troponin I concentrations were measured by ELISA assays. We further detected the correlation of miR-214 and VEGF by molecular and animal assays. MiR-214 was enriched in not only diseased endothelial progenitor cells (EPCs) but also the plasma of coronary artery disease (CAD) patients. Besides, we found out miR-214 was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-214 to the 39-UTR of VEGF mRNA. Knockdown of miR-214 not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but also further promoted blood flow recovery in ischemic limbs of mice. Circulating miR-214 may be a new biomarker for CAD and as a potential diagnostic tool. And increased miR-214 level may be used to predict the presence and severity of coronary lesions in CAD patients.

Phosphoinositide-dependent kinase 1 and mTORC2 synergistically maintain postnatal heart growth and heart function in mice.

The protein kinase Akt plays a critical role in heart function and is activated by phosphorylation of threonine 308 (T308) and serine 473 (S473). While phosphoinositide-dependent kinase 1 (PDK1) is responsible for Akt T308 phosphorylation, the identities of the kinases for Akt S473 phosphorylation in the heart remain controversial. Here, we disrupted mTOR complex 2 (mTORC2) through deletion of Rictor in the heart and found normal heart growth and function. Rictor deletion caused significant reduction of Akt S473 phosphorylation but enhanced Akt T308 phosphorylation, suggesting that a high level of Akt T308 phosphorylation maintains Akt activity and heart function. Deletion of Pdk1 in the heart caused significantly enhanced Akt S473 phosphorylation that was suppressed by removal of Rictor, leading to worsened dilated cardiomyopathy (DCM) and accelerated heart failure in Pdk1-deficient mice. In addition, we found that increasing Akt S473 phosphorylation through deletion of Pten or chemical inhibition of PTEN reversed DCM and heart failure in Pdk1-deficient mice. Investigation of heart samples from human DCM patients revealed changes similar to those in the mouse models. These results demonstrated that PDK1 and mTORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.

S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt.

In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.

Phosphorylation of the Twist1-family basic helix-loop-helix transcription factors is involved in pathological cardiac remodeling.

BACKGROUND: The Twist1-family basic helix-loop-helix (bHLH) transcription factors including Twist1, Hand1 and Hand2, play an essential role in heart development and are implicated in pathological heart remodeling. Previously, it was reported that these bHLH transcription factors can be regulated by phosphorylation within the basic-helix I domain, which is involved in developmental processes such as limb formation and trophoblast differentiation. However, how phosphorylation of Twist1 family functions in post-natal heart is elusive. PRINCIPAL FINDINGS: Here, we generated transgenic mice with over-expression of Hand1 and Twist1 mutants (to mimic or to abolish phosphorylation) in cardiomyocytes and found pathological cardiac remodeling leading to heart failure and sudden death. Gene expression profile analysis revealed up-regulation of growth-promoting genes and down-regulation of metabolic genes. It is well known that aberrant activation of Akt signaling causes pathological cardiac remodeling and results in heart failure. The basic-helix I domain of Twist1 family members contain Akt substrate consensus motif and may be downstream targets of Akt signaling. Using biochemical analysis, we demonstrated that Hand1 and Twist1 were phosphorylated by Akt in the basic-helix I domain. Phosphorylation of Hand1 regulated its transcriptional activation of luciferase reporter genes and DNA binding ability. CONCLUSIONS: This study provides novel insights into the regulation of Twist1 family in cardiac remodeling and suggests that the Twist1 family can be regulated by Akt signaling.

PDK1 plays a critical role in regulating cardiac function in mice and human.

BACKGROUND: PDK1 is an essential protein kinase that plays a critical role in mammalian development. Mouse lacking PDK1 leads to multiple abnormalities and embryonic lethality at E9.5. To elucidate the role of PDK1 in the heart, we investigated the cardiac phenotype of mice that lack PDK1 in the heart in different growth periods and the alteration of PDK1 signaling in human failing heart. METHODS: We employed Cre/loxP system to generate PDK1(flox/flox): α-MHC-Cre mice, which specifically deleted PDK1 in cardiac muscle at birth, and tamoxifen-inducible heart-specific PDK1 knockout mice (PDK1(flox/flox):MerCreMer mice), in which PDK1 was deleted in myocardium in response to the treatment with tamoxifen. Transmural myocardial tissues from human failing hearts and normal hearts were sampled from the left ventricular apex to analyze the activity of PDK1/Akt signaling pathways by Western blotting. RESULTS: PDK1(flox/flox): α-MHC-Cre mice died of heart failure at 5 and 10 weeks old. PDK1(flox/flox) -MerCreMer mice died of heart failure from 5 to 21 weeks after the initiation of tamoxifen treatment at 8 weeks old. We found that expression levels of PDK1 in human failing heart tissues were significantly decreased compared with control hearts. CONCLUSION: Our results suggest that PDK1 signaling network takes part in regulating cardiac viability and function in mice, and may be also involved in human heart failure disease.

Deletion of Akt1 causes heart defects and abnormal cardiomyocyte proliferation.

The PI3K-PDK1-PKB/Akt (PI3K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase 1; PKB, protein kinase B) signaling pathway plays a critical role in a variety of biological processes including cell survival, growth and proliferation, metabolism and organogenesis. Previously, we generated Akt1-deficient mice and found high neonatal mortality with unknown causes. Here we report that histological analysis of Akt1-deficient embryos and newborns revealed heart defects and decreased cell proliferation. Echocardiographic study of Akt1-deficient mice indicated decreased heart function. Further investigation revealed that Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that were heterozygous for a null p38α partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocyte proliferation. Our study suggests that Akt1 is essential for heart development and function, in part, through suppression of p38MAPK activation.

PKB/Akt signaling in heart development and disease.

In mammals, there are three Akt/PKB (protein kinase B) isoforms termed Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma (hereafter referred to as Akt) that are encoded by three distinct genes localized on different chromosomes. Although the three Akt proteins share high homology and display similar domain structures, mouse genetic studies have demonstrated that they play over-lapping but also differential roles in development and physiology. In this review, we summarize recent advances in understanding the roles of Akt signaling in heart development and disease, together with discussion on Akt signaling connection to key signaling pathways in early cardiac specification. The pioneering work on Akt's function in cardiomyocytes performed by Kenneth Walsh's group, was first reported in the new millennium and thus, it is now the right time to look back at some of the discoveries of Akt's role in cardiac biology over the past decade.