Kyung-Duk Min

AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation

AMP-activated protein kinase (AMPK) is an energy-sensing Ser/Thr protein kinase originally shown to be regulated by AMP. AMPK is activated by various cellular stresses that inhibit ATP production or stimulate ATP consumption. In addition to its role in metabolism, AMPK has recently been reported to reshape cells by regulating cell polarity and division. However, the downstream targets of AMPK that participate in these functions have not been fully identified. Here, we show that phosphorylation of the microtubule plus end protein CLIP-170 by AMPK is required for microtubule dynamics and the regulation of directional cell migration. Both inhibition of AMPK and expression of a non-phosphorylatable CLIP-170 mutant resulted in prolonged and enhanced accumulation of CLIP-170 at microtubule tips, and slower tubulin polymerization. Furthermore, inhibition of AMPK impaired microtubule stabilization and perturbed directional cell migration. All of these phenotypes were rescued by expression of a phosphomimetic CLIP-170 mutant. Our results demonstrate, therefore, that AMPK controls basic cellular functions by regulating microtubule dynamics through CLIP-170 phosphorylation.

Identification of genes related to heart failure using global gene expression profiling of human failing myocardium.

Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLK3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure.

Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice

Incretin hormones, including glucagon-like peptide-1 (GLP-1), a target for diabetes mellitus (DM) treatment, are associated with cardioprotection. As dipeptidyl-peptidase IV (DPP-IV) inhibition increases plasma GLP-1 levels in vivo, we investigated the cardioprotective effects of the DPP-IV inhibitor vildagliptin in a murine heart failure (HF) model. We induced transverse aortic constriction (TAC) in C57BL/6J mice, simulating pressure-overloaded cardiac hypertrophy and HF. TAC or sham-operated mice were treated with or without vildagliptin. An intraperitoneal glucose tolerance test revealed that blood glucose levels were higher in the TAC than in sham-operated mice, and these levels improved with vildagliptin administration in both groups. Vildagliptin increased plasma GLP-1 levels in the TAC mice and ameliorated TAC-induced left ventricular enlargement and dysfunction. Vildagliptin palliated both myocardial apoptosis and fibrosis in TAC mice, demonstrated by histological, gene and protein expression analyses, and improved survival rate on day 28 (TAC with vildagliptin, 67.5%; TAC without vildagliptin, 41.5%; P < 0.05). Vildagliptin improved cardiac dysfunction and overall survival in the TAC mice, both by improving impaired glucose tolerance and by increasing GLP-1 levels. DPP-IV inhibitors represent a candidate treatment for HF patients with or without DM.

LEPTIN-REGULATED MOLECULAR NETWORK IS ACTIVATED IN THE LUNG UNDER HEART FAILURE: THE CARDIO-ADIPO-PULMONARY AXIS

Cross-talk between the heart and other organs is a key to unveiling the pathophysiology of heart failure (HF). Although the pulmonary involvement in HF is one of the major comorbidities affecting the morbidity and mortality of patients with HF, its pathophysiology and etiology have not been

Estimating the Prognosis of Patients With Aortic Stenosis in the Current Japanese Population

To estimate the prognosis of AS in the current era, it is also essential to realize that the average age of AS patients has been getting higher as expected lifespan has been prolonged. A recent prospective population-based study demonstrated that the prevalence of AS in 50–59, 60–69, 70–79 and 80–89 year olds was 0.2, 1.3, 3.9 and 9.8%, respectively.2 Also, age-related he importance of estimating the prognosis of patients with aortic stenosis (AS) can not be emphasized too much. Today, aortic valve replacement (AVR) has been established as the standard therapy for symptomatic AS, but alternative therapies such as transcatheter aortic valve replacement (TAVR) are available for high-risk patients who are not eligible for open surgery. However, for the severest patients with a life expectancy <1 year or the chance of “survival with benefit” <25% at 2 years,1 TAVR is also not recommended. Recently, to overcome this clinical discrepancy, the balloon aortic valvuloplasty has been recovered its importance as a bridge therapy to the advanced therapy such as AVR or T