TGF-␤-activated kinase-1 (TAK1), also known as MAPKK kinase-7 (MAP3K7), is a candidate effector of multiple circuits in cardiac biology and disease. Here, we show that inhibition of TAK1 in mice by a cardiac-specific dominant-negative mutation evokes electrophysiological and biochemical properties reminiscent of human Wolff-Parkinson-White syndrome, arising from mutations in AMPactivated protein kinase (AMPK), most notably, accelerated atrioventricular conduction and impaired AMPK activation. To test conclusively the biochemical connection from TAK1 to AMPK suggested by this phenotype, we disrupted TAK1 in mouse embryos and embryonic fibroblasts by Cre-mediated recombination. In TAK1-null embryos, the activating phosphorylation of AMPK at T172 was blocked, accompanied by defective AMPK activity. However, loss of endogenous TAK1 causes midgestation lethality, with defective yolk sac and intraembryonic vasculature. To preclude confounding lethal defects, we acutely ablated floxed TAK1 in culture by viral delivery of Cre. In culture, endogenous TAK1 was activated by oligomycin, the antidiabetic drug metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR), and ischemia, well established triggers of AMPK activity. Loss of TAK1 in culture blocked T172 phosphorylation induced by all three agents, interfered with AMPK activation, impaired phosphorylation of the endogenous AMPK substrate acetyl CoA carboxylase, and also interfered with activation of the AMPK kinase LKB1. Thus, by disrupting the endogenous TAK1 locus, we prove a pivotal role for TAK1 in the LKB1͞AMPK signaling axis, an essential governor of cell metabolism. APKs, MAPKKs (MAP2Ks), and MAP2K kinases (MAP3Ks) comprise a multitiered signaling cascade that couples extracellular cues and intracellular stresses to diverse effector pathways controlling cell growth, survival, transcription, and function (1). Among upstream members of this superfamily, TGF-␤-activated kinase-1 (TAK1)͞MA PKK kinase-7 (MAP3K7) first was identified as a mammalian kinase that complements the lack of Ste11, a MAP3K, in yeast and is activated by TGF-␤ and the relative, bone morphogenetic protein (2). Within the MAPK family, TAK1 is coupled preferentially to JNK and p38. Additional inputs for TAK1 activation include cytokine signaling and innate immunity, and additional outputs include I B kinase ␤ (3). Disruption of TAK1 by saturation mutagenesis in ES cells substantiated that TAK1 is indeed essential for a subset of TGF-␤ effects and also exerts essential functions in signaling by cytokine and Toll-like receptors (3), as proposed on earlier grounds. Additionally, the early-lethal phenotype of TAK1-null embryos, with intraembryonic and yolk sac vascular patterning defects, resembles that of mice devoid of other TGF-␤ signaling proteins, the type I receptor Alk1 and type III receptor endoglin (4).A recognized limitation of germ-line deletions is that potential gene functions may be obscured by early lethality, indirect effects, or secondary adaptations, fueling interest in lineagerestr...

In Taiwan, the prevalence of hyperlipidemia increased due to lifestyle and dietary habit changes. Low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) are all significant predicting factors of coronary artery disease in Taiwan. We recognized that lipid control is especially important in patients with existed atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease (CAD), ischemic stroke and peripheral arterial disease (PAD). Because the risk of ASCVD is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and familial hypercholesterolemia (FH), lipid control is also necessary in these patients. Lifestyle modification is the first step to control lipid. Weight reduction, regular physical exercise and limitation of alcohol intake all reduce triglyceride (TG) levels. Lipid-lowering drugs include HMG-CoA reductase inhibitors (statins), cholesterol absorption inhibitors (ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, nicotinic acids (niacin), fibric acids derivatives (fibrates), and long-chain omega-3 fatty acids. Statin is usually the first line therapy. Combination therapy with statin and other lipid-lowering agents may be considered in some clinical settings. For patients with acute coronary syndrome (ACS) and stable CAD, LDL-C < 70 mg/dL is the major target. A lower target of LDL-C <55 mg/dL can be considered in ACS patients with DM. After treating LDL-C to target, non-HDL-C can be considered as a secondary target for patients with TG ≥ 200 mg/dL. The suggested non-HDL-C target is < 100 mg/dL in ACS and CAD patients. For patients with ischemic stroke or transient ischemic attack presumed to be of atherosclerotic origin, statin therapy is beneficial and LDL-C < 100 mg/dL is the suggested target. For patients with symptomatic carotid stenosis or intracranial arterial stenosis, in addition to antiplatelets and blood pressure control, LDL-C should be lowered to < 100 mg/dL. Statin is necessary for DM patients with CV disease and the LDL-C target is < 70 mg/dL. For diabetic patients who are ≥ 40 years of age, or who are < 40 years of age but have additional CV risk factors, the LDL-C target should be < 100 mg/dL. After achieving LDL-C target, combination of other lipid-lowering agents with statin is reasonable to attain TG < 150 mg/dL and HDL-C >40 in men and >50 mg/dL in women in DM. LDL-C increased CV risk in patients with CKD. In adults with glomerular filtration rate (GFR) < 60 mL/min/1.73m without chronic dialysis (CKD stage 3-5), statin therapy should be initiated if LDL-C ≥ 100 mg/dL. Ezetimibe can be added to statin to consolidate the CV protection in CKD patients. Mutations in LDL receptor, apolipoprotein B and PCSK9 genes are the common causes of FH. Diagnosis of FH usually depends on family history, clinical history of premature CAD, physical findings of xanthoma or corneal arcus and high levels of LDL-C. In addition to conventional lipid lowering therapies, adjunctive treatment with...

In patients with diabetes mellitus (DM), incident cardiovascular (CV) events are associated with poor long-term outcomes. Serum high-sensitivity troponin I (hs-TnI) is widely used to diagnose and predict outcomes in patients with acute coronary syndrome, however, few studies have investigated the accuracy of urine hs-TnI as a predictor for incident CV events in patients with DM. The enrolled participants included patients with DM. Fresh urine hs-TnI levels were measured. Medical records of enrolled patients were used to determine the number of incident CV events prospectively for 3 months. The study cohort comprised 378 participants. We observed significantly higher levels of urine hs-TnI in those with than without subsequent incident CV events. The multivariate logistic regression analysis using different models consistently showed that urine hs-TnI > 4.10 pg/mL was an independent factor predictive of incident CV events. The ROC-AUC analysis revealed that the optimal cutoff value for urine hs-TnI for predicting incident CV events was 1.55 pg/mL and the area was 0.611 (p = 0.027). A single measurement of urinary hs-TnI, collected easily and non-invasively, may be an acceptable biomarker for predicting subsequent incident CV events in patients with DM.

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-activating factor-acetylhydrolase A379V (exon 11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction. J Thromb Haemost 2006; 4: 1023-8.Summary. Background: Oxidation of low density lipoproteins is an initial step of atherogenesis that generates pro-inflammatory phospholipids, including platelet-activating factor (PAF). PAF is degraded by PAF-acetylhydrolase (PAF-AH), which has been postulated to be a risk factor for myocardial infarction (MI). The role of PAF-AH for the onset of premature MI is unclear. Methods: Polymorphisms located in putatively functional regions were investigated in a cohort of patients having premature MI onset prior to 46 years of age (n ¼ 200) and a sex-age-matched control group (n ¼ 200). The activity of PAF-AH and coronary angiograms were evaluated for the severity of coronary atherosclerosis. Results: The V allele of A379V (exon 11) polymorphism on PAF-AH gene was more frequent in patients with premature MI (P ¼ 0.001). This V allele polymorphism was also associated with a lower activity of plasma PAF-AH and a more complex coronary atherosclerosis (p Trends <0.05). Multiple logistic regression analysis showed that this polymorphism was an independent risk factor (Odds Ratio [OR] 1.66, 95% CI 1.14.1 to 5.80, P ¼ 0.008) as well as smoking (OR 3.72, 95% CI 1.77 to 9.28, P ¼ 0.001), diabetes mellitus (OR 2.25, 95% CI 1.40 to 5.32, P ¼ 0.007) and hypertension (OR 1.88, 95% CI 1.25 to 5.36, P ¼ 0.003) for the onset of premature MI. Conclusion: We conclude that a functional and significant association between the A379V polymorphism on exon 11 of PAF-AH gene and premature MI exists in this Taiwanese population. This polymorphism is significantly associated with the PAF-AH activity and the severity of coronary atherosclerosis.