Yoshiko Mizuno

Positive and Negative Regulation of the Cardiovascular Transcription Factor KLF5 by p300 and the Oncogenic Regulator SET through Interaction and Acetylation on the DNA-Binding Domain

ABSTRACT Here we show a novel pathway of transcriptional regulation of a DNA-binding transcription factor by coupled interaction and modification (e.g., acetylation) through the DNA-binding domain (DBD). The oncogenic regulator SET was isolated by affinity purification of factors interacting with the DBD of the cardiovascular transcription factor KLF5. SET negatively regulated KLF5 DNA binding, transactivation, and cell-proliferative activities. Down-regulation of the negative regulator SET was seen in response to KLF5-mediated gene activation. The coactivator/acetylase p300, on the other hand, interacted with and acetylated KLF5 DBD, and activated its transcription. Interestingly, SET inhibited KLF5 acetylation, and a nonacetylated mutant of KLF5 showed reduced transcriptional activation and cell growth complementary to the actions of SET. These findings suggest a new pathway for regulation of a DNA-binding transcription factor on the DBD through interaction and coupled acetylation by two opposing regulatory factors of a coactivator/acetylase and a negative cofactor harboring activity to inhibit acetylation.

Relationship of Left Ventricular Diastolic Function to Obesity and Overweight in a Japanese Population With Preserved Left Ventricular Ejection Fraction

BACKGROUNDnObesity has been found to be associated with future development of diastolic heart failure. Other evidence has indicated that the effect of obesity on left ventricular (LV) mass varies among ethnicities. However, there are few data on the relationship between body mass index (BMI) and LV diastolic dysfunction in the Japanese population.nnnMETHODSANDRESULTSnWe performed echocardiography in 788 subjects without valvular disease or LV systolic dysfunction. They were divided into 3 groups by BMI: normal weight, overweight, and obese. We used multivariable linear regression analysis to assess the clinical variables associated with diastolic parameters, including BMI. We also assessed the risk of diastolic dysfunction associated with BMI using multivariable logistic models. Overweight and obese subjects had significantly worse LV diastolic function and greater LV mass than normal weight subjects. In the multivariable analysis, BMI was independently associated with diastolic parameters. Furthermore, after adjusting for clinical factors, the increased risks of diastolic dysfunction in overweight subjects (adjusted odds ratio: 2.02, 95% confidence interval 1.21-3.36) and obese subjects (4.85, 3.36-16.27) were greater than those previously observed in Western populations.nnnCONCLUSIONSnThe Japanese population might be more susceptible than Western subjects to the effect of BMI on LV diastolic function. Differences between ethnicities should be taken into consideration in strategies for the prevention of diastolic heart failure. (Circ J 2016; 80: 1951-1956).

Early menopause does not influence left ventricular diastolic dysfunction: A clinical observational study in healthy subjects

BACKGROUNDnThe prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after their 50s and may contribute to the high prevalence of diastolic heart failure in elderly women. A decrease in estrogen levels after menopause is postulated to be one of the mechanisms responsible for this phenomenon. However, there is a paucity of data on the relationship between the timing of menopause and the progression of LVDD in the clinical setting; thus, we investigated this relationship in healthy postmenopausal women.nnnMETHODSnWe enrolled 115 women and divided them into two groups according to median menopause age: 61 who experienced menopause at ≤50 years (early menopause group), and 54 who experienced menopause at >50 years (late menopause group). We compared the echocardiographic and clinical characteristics between the two groups.nnnRESULTSnThere were no significant differences in LV diastolic parameters (mitral E/A, p=0.561; e, p=0.052; E/e, p=0.081; DCT, p=0.082; prevalence of LVDD class, p=0.801), as well as other echocardiographic parameters and clinical characteristics between the two groups. Multivariate linear regression analysis showed that the independent determinants of LVDD were age and body mass index, but not the timing of menopause.nnnCONCLUSIONSnEarly menopause did not influence the progression of LVDD in postmenopausal women. The sharp progression of LVDD in elderly women is complex and probably influenced by multiple factors.

Factors influencing left atrial volume in a population with preserved ejection fraction: Left ventricular diastolic dysfunction or clinical factors?

BACKGROUNDnIncreased left atrial volume (LAV) predicts a higher incidence of cardiovascular events and is widely recognized as a major surrogate marker of left ventricular (LV) diastolic dysfunction (DD). Although the pathophysiology of LA enlargement is probably multifactorial, few studies have examined comprehensively the clinical factors that lead to LA enlargement in the absence of valvular disease or LV systolic dysfunction. Therefore, we investigated associations between LAV and several clinical and echocardiographic parameters including DD.nnnMETHODSnWe enrolled 557 subjects without significant valve disease or LV systolic dysfunction from the health check-up clinic retrospectively. We performed univariable and multivariable linear regression using lnLAV index as the dependent variable and the following independent variables: gender, age, smoking status, drinking habit, hypertension, diabetes, body mass index (BMI), LV ejection fraction, DD, LV mass index, hemoglobin, serum creatinine, serum total cholesterol, serum uric acid, serum sodium, and serum iron.nnnRESULTSnIn multivariable analysis, LAV index was independently associated with BMI, lower hemoglobin, and moderate and severe DD compared with normal diastolic function (p<0.001), but not with mild DD (p=0.70).nnnCONCLUSIONSnLA enlargement was independently associated with moderate and severe DD, but not with mild DD. Furthermore, obesity and lower hemoglobin were associated with LAV independently of DD.

Association of subclinical carotid atherosclerosis with immediate memory and other cognitive functions

To clarify whether carotid atherosclerosis and its risk factors are associated with cognitive decline.

Beneficial effect of body weight control on left ventricular diastolic function in the general population: an analysis of longitudinal data from a health check-up clinic

AimsnLeft ventricular (LV) diastolic dysfunction may lead to heart failure. A high body mass index (BMI) is associated with worse LV diastolic function. However, knowledge of the longitudinal relation between changes in BMI and LV diastolic function is limited.nnnMethods and resultsnWe retrospectively identified 165 asymptomatic individuals (aged 60u2009±u200910u2009years, 55% male) with preserved LV ejection fraction, who underwent repeated health check-ups (median interval: 365u2009days) at our hospital between 2009 and 2012. The longitudinal data were analysed using a linear mixed-effects model adjusted for important clinical variables at baseline to evaluate the associations between changes in BMI and LV diastolic function from one visit to the next. Baseline characteristics were BMI, 23u2009±u20093u2009kg/m2; E/E ratio, 9u2009±u20092; E velocity, 8u2009±u20092u2009cm/s; and left atrial (LA) volume index, 26u2009±u20098u2009mL/m2. Eighty-two of our participants had baseline LV diastolic dysfunction. In multivariable analyses, a BMI change was associated with a change in LV diastolic function. A one-unit decrease in BMI between consecutive visits corresponded to an average decrease in LA volume index of 0.80u2009mL/m2 (95% confidence interval: 0.38, 1.23; Pu2009<u20090.001), a decrease in E/Eratio of 0.11 (-0.015, 0.23; Pu2009=u20090.086), and an increase in E velocity of 0.11u2009cm/s (0.18, 0.031; Pu2009=u20090.006).nnnConclusionnOur study showed that there was an association between changes in BMI and LV diastolic function. A decrease in BMI corresponded to a significant decrease in LA volume index and a significant increase in E velocity.

Usefulness of Carotid Arterial Strain Values for Evaluating the Arteriosclerosis

Aim: We investigated the clinical usefulness of carotid arterial strain and the strain rate for evaluating the progression of arteriosclerosis measured using a two-dimensional speckle-tracking method in carotid ultrasonography. Methods: We enrolled 259 participants (age: 64 ± 12 years; men: 149; women: 110) in this retrospective analysis. The circumferential strain and the strain rate were measured in bilateral common carotid arteries, and the lowest values were used for the analyses. To assess the characteristics of strain and the strain rate, we investigated the associations between the strain values and gender, age, body mass index (BMI), blood pressure (BP), and the presence of hypertension, diabetes mellitus, and hyperlipidemia. We also examined the explanatory factors for the strain values using clinical parameters along with the intima-media thickness (IMT), the ankle brachial index (ABI), and the cardio-ankle vascular index (CAVI) as possible candidates. Finally, we investigated whether the strain values might be an independent predictor for vascular diseases using multivariate logistic regression analyses. Results: The carotid circumferential strain and the strain rate were significantly correlated with age, IMT, and the CAVI, but not with the BMI, BP, or ABI. Strain and the strain rates were lower in participants with hypertension or cerebrovascular disease and were selected as significant predictive factors for the presence of cerebrovascular diseases, together with diabetes and the CAVI. Conclusions: Strain and the strain rate of carotid arteries, which could represent local arterial stiffness, might be associated with atherosclerosis and could possibly be used to predict cerebrovascular disease.