[Associations Between Insulin Resistance Indexes and Hyperuricemia in Hypertensive Population].

Objective To explore the relationship between insulin resistance (IR) indexes and hyperuricemia (HUA) among the people with hypertension. Methods From July to August in 2018,hypertension screening was carried out in Wuyuan county,Jiangxi province,and the data were collected through questionnaire survey,physical measurement,and biochemical test.Logistic regression was performed to analyze the relationship between HUA and IR indexes including metabolic score for IR (METS-IR),triglyceride-glucose (TyG) index,TyG-body mass index (BMI),TyG-waist circumference (WC),visceral adiposity index (VAI),triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C),and lipid accumulation product (LAP).The penalty spline method was used for the curve fitting between IR indexes and HUA.The area under the receiver operating characteristic curve (AUC) was employed to reveal the correlation between each index and HUA. Results The 14 220 hypertension patients included 6 713 males and 7 507 females,with the average age of (63.8±9.4) years old,the average uric acid level of (418.9±120.6) mmol/L,and the HUA detection rate of 44.4%.The HUA group had higher proportions of males,current drinking,current smoking,diabetes,and using antihypertensive drugs,older age,higher diastolic blood pressure,WC,BMI,homocysteine,total cholesterol,TG,low-density lipoprotein cholesterol,blood urea nitrogen,creatinine,aspartate aminotransferase,alanine aminotransferase,total protein,albumin,total bilirubin,direct bilirubin, METS-IR, TyG, TyG-BMI, TyG-WC, VAI, TG/HDL-C, and LAP, and lower systolic blood pressure and HDL-C than the normal uric acid group (all P<0.05).Multivariate Logistic regression showed that METS-IR (OR=1.049,95%CI=1.038-1.060, P<0.001), TyG (OR=1.639,95%CI=1.496-1.797, P<0.001), TyG-BMI (OR=1.008,95%CI=1.006-1.010, P<0.001), TyG-WC (OR=1.003,95%CI=1.002-1.004, P<0.001), lnVAI (OR=1.850, 95%CI=1.735-1.973, P<0.001), ln(TG/HDL-C) (OR=1.862,95%CI=1.692-2.048, P<0.001),and lnLAP (OR=1.503,95%CI=1.401-1.613,P<0.001) were associated with the risk of HUA.Curve fitting indicated that METS-IR,TyG,TYG-BMI,TYG-WC,lnVAI,ln(TG/HDL-C),and lnLAP were positively correlated with HUA (all P<0.001),and the AUC of TyG index was higher than that of other IR indexes (all P<0.05). Conclusion Increased IR indexes,especially TyG,were associated with the risk of HUA among people with hypertension.

Hsp22 ameliorates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidative stress, and apoptosis.

Sepsis-induced myocardial dysfunction (SIMD) is ubiquitous in septic shock patients and is associated with high morbidity and mortality rates. Heat shock protein 22 (Hsp22), which belongs to the small HSP family of proteins, is involved in several biological functions. However, the function of Hsp22 in lipopolysaccharide (LPS)-induced myocardial injury is not yet established. This study was aimed at investigating the underlying mechanistic aspects of Hsp22 in myocardial injury induced by LPS. In this study, following the random assignment of male C57BL/6 mice into control, LPS-treated, and LPS + Hsp22 treated groups, relevant echocardiograms and staining were performed to scrutinize the cardiac pathology. Plausible mechanisms were proposed based on the findings of the enzyme-linked immunosorbent assay and Western blotting assay. A protective role of Hsp22 against LPS-induced myocardial injury emerged, as evidenced from decreased levels of creatinine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and enhanced cardiac function. The post-LPS administration-caused spike in inflammatory cytokines (IL-1ß, IL-6, TNF-α and NLRP3) was attenuated by the Hsp22 pre-treatment. In addition, superoxide dismutase (SOD) activity and B-cell lymphoma-2 (Bcl2) levels were augmented by Hsp22 treatment resulting in lowering of LPS-induced oxidative stress and cardiomyocyte apoptosis. In summary, the suppression of LPS-induced myocardial injury by Hsp22 overexpression via targeting of inflammation, oxidative stress, and apoptosis in cardiomyocytes paves the way for this protein to be employed in the therapy of SIMD.

De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy.

Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy.

Potential Target Genes in the Development of Atrial Fibrillation: A Comprehensive Bioinformatics Analysis.

BACKGROUND Atrial fibrillation (AF) is the most prevalent arrhythmia worldwide. Although it is not life-threatening, the accompanying rapid and irregular ventricular rate can lead to hemodynamic deterioration and obvious symptoms, especially the risk of cerebrovascular embolism. Our study aimed to identify novel and promising genes that could explain the underlying mechanism of AF development. MATERIAL AND METHODS Expression profiles GSE41177, GSE79768, and GSE14975 were acquired from the Gene Expression Omnibus Database. R software was used for identifying differentially expressed genes (DEGs), and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were subsequently performed. A protein-protein interaction network was constructed in Cytoscape software. Next, a least absolute shrinkage and selection operator (LASSO) model was constructed and receiver-operating characteristic curve analysis was conducted to assess the specificity and sensitivity of the key genes. RESULTS We obtained 204 DEGs from the datasets. The DEGs were mostly involved in immune response and cell communication. The primary pathways of the DEGs were related to the course or maintenance of autoimmune and chronic inflammatory diseases. The top 20 hub genes (high scores in cytoHubba) were selected in the PPI network. Finally, we identified 6 key genes (FCGR3B, CLEC10A, FPR2, IGSF6, S100A9, and S100A12) via the LASSO model. CONCLUSIONS We present 6 target genes that are potentially involved in the molecular mechanisms of AF development. In addition, these genes are likely to serve as potential therapeutic targets.

Novel Approaches for the Treatment of Familial Hypercholesterolemia: Current Status and Future Challenges.

Familial hypercholesterolemia (FH) is an autosomal-dominant disorder that is characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and an increased risk of cardiovascular disease. Despite the use of high-dose statins and the recent addition of proprotein convertase subtilisin/kexin type 9 inhibitors as a treatment option, many patients with homozygous FH fail to achieve optimal reductions of LDL-c levels. Gene therapy has become one of the most promising research directions for contemporary life sciences and is a potential treatment option for FH. Recent studies have confirmed the efficacy of a recombinant adeno-associated virus 8 vector expressing the human LDL-c receptor gene in a mouse model, and this vector is currently in phase 2 clinical trials. Much progress has also been achieved in the fields of antisense oligonucleotide- and small interfering RNA-based gene therapies, which are in phase 1-2 clinical trials. In addition, novel approaches, such as the use of minicircle DNA vectors, microRNAs, long non-coding RNAs, and the CRISPR/Cas9 gene-editing system, have shown great potential for FH therapy. However, the delivery system, immunogenicity, accuracy, and specificity of gene therapies limit their clinical applications. In this article, we discuss the current status of gene therapy and recent advances that will likely affect the clinical application of gene therapy for the treatment of FH.

Aerobic exercise improves endothelial function and serum adropin levels in obese adolescents independent of body weight loss.

Adropin is a secreted protein that regulates endothelial function. However, adropin levels in obese adolescent patients are currently uncertain. Therefore, we evaluated the association between plasma adropin levels and vascular endothelial function and investigated the effect of aerobic exercise in obese adolescents. A total of 45 obese adolescents and 20 controls (age 16-19 years) were included in our study. The obese adolescents received 12 weeks of aerobic exercise training. Serum adropin was detected using enzyme-linked immunosorbent assay. Vascular reactive hyperemia indexes (RHIs) were obtained using Endo-PAT2000. Adropin levels and RHI were significantly lower in obese adolescents than in normal-weight adolescents. Adropin levels and RHI increased significantly independently of changes in body weight after an exercise intervention (P < 0.01). Pearson correlation analysis revealed that adropin levels positively correlated with HDL-C levels (r = 0.389, P < 0.01) and RHI (r = 0.32, P < 0.01). Multiple linear stepwise regression analysis showed that the insulin resistance index (t = -3.301, P < 0.01) and HDL-C level (t = 2.620, P = 0.011) were independent risk factors of adropin levels. In addition, Δadropin (t = 3.261, P < 0.01) was an independent influencing factor of ΔRHI. Our findings suggest that adropin plays an important role in vascular endothelial function in obese adolescents.

Independent association between age and circadian systolic blood pressure patterns in adults with hypertension.

Previous studies indicate a preliminary association between age and circadian blood pressure (BP) variation. This association would be affected by confounding factors in real-world populations. The authors investigated whether this is a convincingly independent association in a real-world population of adults with hypertension. Clinical data and findings of 24-hour ambulatory BP monitoring were obtained from 297 consecutive adults with hypertension (60.19±0.77 years). BP dipping patterns were categorized based on the percentage of nocturnal BP drop. Multivariate linear regression analysis identified an independent correlation between age and percentage of nocturnal systolic BPdrop (ß=-7.296; 95% CI, -10.430 to -4.162 [P<.001]). Reverse dippers were the oldest and extreme dippers were the youngest. A significant age difference was noted among patients grouped into four BP dipping patterns with and without adjustments for sex, body mass index, drugs, diabetes mellitus, smoking, 24-hour mean heart rate, and 24-hour mean systolic and diastolic BP.

MicroRNA let-7g inhibited hypoxia-induced proliferation of PASMCs via G0/G1 cell cycle arrest by targeting c-myc.

AIMS: Pulmonary hypertension (PH) is a proliferative disorder characterized by enhanced proliferation and suppressed apoptosis of intrapulmonary vascular smooth muscle cells. Recently, network-based bioinformatics have identified let-7 family, a tumor suppressive microRNA, regulate multiple interacting targets relevant to PH. However, the role of let-7 in vascular homeostasis in PH remains unknown. Thus, we wanted to investigate the role of let-7 in hypoxia-induced PASMCs proliferation and the underlying mechanism in hypoxic pulmonary hypertension (HPH). MAIN METHODS: The male Sprague-Dawley (SD) rats were exposed to hypoxia (10% O2) for 21days to induce HPH. The expression of let-7 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Primary rat PASMCs were exposed to hypoxia (3% O2). MTS and EDU were performed to evaluate PASMCs proliferation. The mRNA and protein expression of c-myc, Bmi-1 and p16 were determined by qRT-PCR and Western blotting, respectively. The functions of let-7g on PASMCs proliferation, c-myc, Bmi-1 and p16 expression were assessed by let-7g mimic and inhibitor transfection. KEY FINDINGS: Among let-7 family members, only let-7b and let-7g were significantly down-regulated in remodeled pulmonary artery in HPH rats. Furthermore, only let-7g level was decreased in hypoxic PASMCs. Either hypoxia or let-7g inhibitor stimulated proliferation of PASMCs, let-7g mimic inhibited hypoxia-induced PASMCs proliferation. C-myc was the target of let-7g in PASMCs. Transfect of let-7g mimic inhibited hypoxia-induced c-myc, Bmi-1 up-regulation and p16 down-regulation, which ultimately controls cell cycle progression. SIGNIFICANCE: Loss of inhibition on c-myc-Bmi-1-p16 signaling pathway by let-7g may lead to PASMCs proliferation and vascular remodeling in HPH.

NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway.

Neurensin-2 (NRSN2), a small neural membrane protein which localized in small vesicles in neural cells. Recent report suggested that Neurensin-2 might play a suppressive role in tumor. While the biological functions and molecular mechanisms in cancer progression remain unknown. We retrieved Oncomine Database and found that NRSN2 is commonly highly expressed in non-small cell lung cancer (NSCLC). We examined the levels of NRSN2 in 18 pairs of NSCLC and adjacent tissues and found that NRSN2 was overexpressed in malignant tissues. Both loss and gain of function experiments in NSCLC cell lines suggest that NRSN2 promotes cell growth, but no effects in cell invasion. Further investigation show that NRSN2 could affect phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling. Taken together, our findings suggest that NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway.

MicroRNA-223 displays a protective role against cardiomyocyte hypertrophy by targeting cardiac troponin I-interacting kinase.

BACKGROUND/AIMS: MicroRNAs play regulatory role in cardiovascular disease. MicroRNA-223 (miR-223) was found to be expressed abundantly in myocardium. TNNI3K, a novel cardiac troponin I (cTnI)-interacting and cardiac hypertrophy related kinase, is computationally predicted as a potential target of miR-223. This study was designed to investigate the cellular and molecular effects of miR-223 on cardiomyoctye hypertrophy, focusing on the role of TNNI3K. METHODS: Neonatal rat cardiomyocytes (CMs) were cultured, and CMs hypertrophy was induced by endothelin-1 (ET-1). In vivo cardiac hypertrophy was induced by transverse aorta constriction (TAC) in rats. Expression of miR-223 in CMs and myocardium was detected by real-time PCR (RT-PCR). MiR-223 and TNNI3K were overexpressed in CMs via chemically modifed sense RNA (miR-223 mimic) transfection or recombinant adenovirus infection, respectively. Cell size was measured by surface area calculation using fluorescence microscopy after anti-α-actinin staining. Expression of hypertrophy-related genes was detected by RT-PCR. The protein expression of TNNI3K and cTnI was determined by Western blots. Luciferase assay was employed to confirm the direct binding of miR-223 to the 3'UTR of TNNI3K mRNA. Intracellular calcium was measured by sensitive fluorescent indicator (Furo-2). Video-based edge detection system was employed to measure cardiomyocyte contractility. RESULTS: MiR-223 was downregulated in ET-1 induced hypertrophic CMs and in hypertrophic myocardium compared with respective controls. MiR-223 overexpression in CMs alleviated ET-1 induced hypertrophy, evidenced by smaller cell surface area and downregulated ANP, α-actinin, Myh6 and Myh7 expression. Luciferase reporter gene assay showed that TNNI3K serves as a direct target gene of miR-223. In miR-223-overexpressed CMs, the protein expression of TNNI3K was significantly downregulated. MiR-223 overexpression also rescued the upregulated TNNI3K expression in hypertrophic CMs. Furthermore, cTnI phosphorylation was downregulated post miR-223 overexpression. Ad.rTNNI3K increased intracellular Ca(2+) concentrations and cell shortening in CMs, while miR-223 overexpression significantly rescued these hypertrophic effects. CONCLUSION: By direct targeting TNNI3K, miR-223 could suppress CMs hypertrophy via downregulating cTnI phosphorylation, reducing intracellular Ca(2+) and contractility of CMs. miR-223 / TNNI3K axis may thus be major players of CMs hypertrophy.

Rapamycin protects cardiomyocytes against anoxia/reoxygenation injury by inducing autophagy through the PI3k/Akt pathway.

The purpose of this study was to investigate the potential cardioprotection roles of Rapamycin in anoxia/reoxygenation (A/R) injury of cardiomyocytes through inducing autophagy, and the involvement of PI3k/Akt pathway. We employed simulated A/R of neonatal rat ventricular myocytes (NRVM) as an in vitro model of ischemial/reperfusion (I/R) injury to the heart. NRVM were pretreated with four different concentrations of Rapamycin (20, 50, 100, 150 µmol/L), and pretreated with 10 mmol/L 3-methyladenine (3MA) for inhibiting autophagy during A/R. Then, Western blot analysis was used to examine variation in the expression of LC3-II, LC3-I, Bim, caspase-3, p-PI3KI, PI3KI, p-Akt and Akt. In our model, Rapamycin had a preferential action on autophagy, increasing the expression of LC3-II/LC3-I, whereas decreasing the expression of Bim and caspase-3. Moreover, our results also demonstrated that Rapamycin inhibited the activation of p-PI3KI and enhanced the activation of p-Akt. It is concluded that Rapamycin has a cardioprotection effect by inducing autophagy in a concentration-dependent manner against apopotosis through PI3K/Akt signaling pathway during A/R in NRVM.

New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant. RESULTS: Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10-15). CONCLUSIONS: This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants.

ERK5 knock down aggravates detrimental effects of hypothermal stimulation on cardiomyocytes via Bim upregulation.

Mechanism of cold induced myocardial injury remained unclear. Our study investigated the role of ERK5/Bim pathway in hypothermal stimulation-induced apoptosis or damage of cardiomyocytes (CMs). Results showed that in CMs which under hypothermal stimulation, ERK5 siRNA promoted expression of Bim protein. Bim siRNA did not influence ERK5 expression but attenuated production of p-ERK5. ERK5 siRNA induced higher apoptosis rate; intracellular Ca(2+) overload; ROS activity; ΔΨm damage in hypothermia stimulated CMs, when compared with hypothermal stimulation solely treated group, while Bim siRNA effected oppositely and canceled pro-apoptotic effect of ERK5 siRNA. In conclusion, ERK5 knock down releases inhibition to Bim expression, induces aggravated apoptosis in CMs under hypothermal stimulation, which related to higher intracellular Ca(2+) overload, ROS activity, and more severe ΔΨm damage. Results revealed regulative role of ERK5/Bim pathway in hypothermal stimulation-induced injure or apoptosis of cardiomyocytes.

[SCN5A mutation in patients with Brugada electrocardiographic pattern induced by fever].

OBJECTIVE: To explore the relationship between SCN5A, SCN1b, SCN3b and GPD1L genotypes and the risk of malignant arrhythmia in patients with Brugada electrocardiographic pattern induced by fever. METHODS: The clinical data and peripheral blood of patients with Brugada electrocardiographic pattern induced by fever were collected. Patients with depolarization abnormality associated with hypertension, coronary heart disease, drugs and other factors were excluded. The direct DNA sequencing was used to screen the mutation of candidate gene SCN5A, SCN1b, SCN3b and GPD1L. If gene variation was found, mutation or polymorphism was then determined by comparison with 200 control individuals. The relationship between genotype and phenotype as well as the risk of malignant arrhythmia were analyzed. RESULTS: Five eligible patients with fever-induced Brugada ECG pattern were included in this study. TypeI Brugada ECG was presented in all five patients in fibrile state and disappeared in normothermia. No sudden cardiac death (SCD) occurred and no ventricular arrhythmia was presented in Holter monitor during the 3 to 5 years follow-up period. Six gene variants were found including a novel missense mutation of base C to T, named Arg965 Cys (R965C), which located in 965 codon of the 17 exon in SCN5A, and five SCN5A polymorphisms including A29A (c.87A>G), R1193Q (c.3578G>A), D1819D (c.5457T>C), exon11 -24G>A, exon23 +4A>G. CONCLUSION: SCN5A mutation is related to fever-induced Brugada ECG pattern. However, individuals with Brugada ECG pattern induced by fever bear low risk of malignant arrhythmia and SCD during fibrile state and follow up in this small patient cohort.

[The protection of heme oxygenase-1 from acute cardiocyte injury in rats].

OBJECTIVE: To observe the protection of Heme oxygenase-1 (HO-1) from lipopolysaccharide (LPS)-induced cardiocyte injury and its mechanism. METHODS: Cardiocyte was isolated from SD neonate rat and cultured in vitro, and was divided into control group (normal culture), LPS group (with stimulation of 30 micromoL/L LPS for 1 hour), LPS + Hemin group (with same treatment to LPS group after stimulation of 5 micromoL/L Hemin for 1 hour), and LPS + ZnPP group (with same treatment to LPS group after stimulation of 3 micromoL/L ZnPP for 1 hour). The level of lactic-dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) were measured by thio-barbituric acid and xanthine oxidase techniques. The cell heart rhythm, survival rate and apoptosis rate were examined. The expressions of nuclear factor kappaB (NF-kappaB), HO-1 and tumor necrosis factor-alpha (TNF-alpha) were measured with Western blotting. The HO-1 mRNA was examined by RT-PCR. RESULTS: The level of LDH and MDA in LPS, LPS + Hemin, and LPS + ZnPP groups were (113 +/- 15), (79 +/- 13), (154 +/- 22) U/L, and (1.88 +/- 0.36), (1.16 +/- 0.32), (2.84 +/- 0.44) mmoL/L respectively, which were all obviously higher than those in control group [(69 +/- 10) U/L, (0.87 +/- 0.25) mmol/L, P < 0.05]. The level of SOD in LPS, PS + Hemin, and LPS + ZnPP groups (17.8 +/- 1.8, 22.5 +/- 2.4, 13.4 +/- 1.5 U/mL, respectively) was all obviously lower than that in control group (24.3 +/- 3.6 U/mL, P < 0.05). The apoptosis rate and heart rhythm were obviously higher and survival rate significantly lower in LPS, LPS + Hemin, and LPS + ZnPP groups than those in control group (P < 0.05). The level of HO-1mRNA in LPS, LPS + Hemin, and LPS + ZnPP groups was higher than that in control group (P < 0.01), among which LPS + Hemin group was the highest. The level of HO-1, TNF-alpha and NF-kappaB in LPS, LPS + Hemin, and LPS + ZnPP groups was higher than those in control group (P < 0.05), among which the level of HO-1 protein in LPS + Hemin group was the highest, the level of TNF-alpha and NF-kappaB in LPS + ZnPP group was highest. CONCLUSION: LPS can induce cardiocyte injury, which can be inhibited through the anti-inflammatory, anti-oxidant, and anti-apoptosis functions by HO-1.

Overexpression of TNNI3K, a cardiac-specific MAP kinase, promotes P19CL6-derived cardiac myogenesis and prevents myocardial infarction-induced injury.

TNNI3K is a new cardiac-specific MAP kinase whose gene is localized to 1p31.1 and that belongs to a tyrosine kinase-like branch in the kinase tree of the human genome. In the present study we investigated the role of TNNI3K in the cardiac myogenesis process and in the repair of ischemic injury. Pluripotent P19CL6 cells with or without transfection by pcDNA6-TNNI3K plasmid were used to induce differentiation into beating cardiomyocytes. TNNI3K promoted the differentiation process, judging from the increasing beating mass and increased number of alpha-actinin-positive cells. TNNI3K improved cardiac function by enhancing beating frequency and increasing the contractile force and epinephrine response of spontaneous action potentials without an increase of the single-cell size. TNNI3K suppressed phosphorylation of cardiac troponin I, annexin-V(+) cells, Bax protein, and p38/JNK-mediated apoptosis. Intramyocardial administration of TNNI3K-overexpressing P19CL6 cells in mice with myocardial infarction improved cardiac performance and attenuated ventricular remodeling compared with injection of wild-type P19CL6 cells. In conclusion, our study clearly indicates that TNNI3K promotes cardiomyogenesis, enhances cardiac performance, and protects the myocardium from ischemic injury by suppressing p38/JNK-mediated apoptosis. Therefore, modulation of TNNI3K activity would be a useful therapeutic approach for ischemic cardiac disease.