Does Kruppel Like Factor 15 Play an Important Role in the Left Ventricular Hypertrophy of Patients with Type 2 Diabetes?
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ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC5478200 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
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Does Krüppel Like Factor 15 Play an Important Role in the Left Ventricular Hypertrophy of Patients with Type 2 Diabetes?
EBioMedicine 20170508
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Project description:Left ventricular hypertrophy (LVH) is an independent risk factor for adverse cardiovascular events and is often present in patients with hypertension. Treatment to reduce blood pressure and regress LVH is key to improving health outcomes, but currently available drugs have only modest cardioprotective effects. Improved understanding of the molecular mechanisms involved in the development of LVH may lead to new therapeutic targets in the future. There is now compelling evidence that the transcription factor Kruppel-like factor 15 (KLF15) is an important negative regulator of cardiac hypertrophy in both experimental models and in man. Studies have reported that loss or suppression of KLF15 contributes to LVH, through lack of inhibition of pro-hypertrophic transcription factors and stimulation of trophic and fibrotic signaling pathways. This review provides a summary of the experimental and human studies that have investigated the role of KLF15 in the development of cardiac hypertrophy. It also discusses our recent paper that described the contribution of genetic variants in KLF15 to the development of LVH and heart failure in high-risk patients.
| S-EPMC5983718 | biostudies-literature
Project description:Left ventricular (LV) hypertrophy (LVH) is a heritable trait that is common in type 2 diabetes and is associated with the development of heart failure. The transcriptional factor Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy in experimental models. This study investigated if KLF15 gene variants were associated with LVH in type 2 diabetes. In stage 1 of a 2-stage approach, patients with type 2 diabetes and no known cardiac disease were prospectively recruited for a transthoracic echocardiographic assessment (Melbourne Diabetes Heart Cohort) (n=318) and genotyping of two KLF15 single nucleotide polymorphisms (SNPs) (rs9838915, rs6796325). In stage 2, the association of KLF15 SNPs with LVH was investigated in the Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) type 2 diabetes cohort (n=5631). The KLF15 SNP rs9838915 A allele was associated in a dominant manner with LV mass before (P=0.003) and after (P=0.001) adjustment for age, gender, body mass index (BMI) and hypertension, and with adjusted septal (P<0.0001) and posterior (P=0.004) wall thickness. LVH was present in 35% of patients. Over a median follow up of 5.6years, there were 22 (7%) first heart failure hospitalizations. The adjusted risk of heart failure hospitalization was 5.5-fold greater in those with LVH and the rs9838915 A allele compared to those without LVH and the GG genotype (hazard ratio (HR) 5.5 (1.6-18.6), P=0.006). The association of rs9838915 A allele with LVH was replicated in the Go-DARTS cohort. We have identified the KLF15 SNP rs9838915 A allele as a marker of LVH in patients with type 2 diabetes, and replicated these findings in a large independent cohort. Studies are needed to characterize the functional importance of these results, and to determine if the SNP rs9838915 A allele is associated with LVH in other high risk patient cohorts.
| S-EPMC5405178 | biostudies-literature
Project description:Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.
| S-EPMC1855421 | biostudies-literature
Project description: Not available
| S-EPMC11241903 | biostudies-literature
Project description:In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ?65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (? = 6.71 [95% CI 4.35-9.01] g per doubling of FGF23). 32% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM ? = 9.71 [95% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (? = 3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97-1.48]).In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
| S-EPMC3840534 | biostudies-literature
Project description:Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
| S-EPMC3204831 | biostudies-literature
Project description:Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.
| S-EPMC4670583 | biostudies-literature
Project description:The molecular mechanism underlying cardiac remodeling following exercise have been incompletely understood. Until now, most studies have been performed in rodents. We studied cardiac remodeling in the physiologically more relevant animal model, the swine. Microarray analysis was performed on animals that underwent either and exercise protocol or remained sedentary. RNA was isolated from tissue samples from the endocardial layer of the free wall of the left ventricle. RNA was isolated from 8 exercise-trained and 8 sedentary animals 4-5 weeks after start of the protocol. Each group contained 4 males and 4 females. Animals used for the study were 2-3 months old Yorkshire x Landrace swine. Only neutered males entered the study.
2014-06-01 | E-GEOD-37922 | biostudies-arrayexpress
Project description:Left ventricular (LV) hypertrophy is a strong independent predictor of increased cardiovascular morbidity and mortality in clinical and population-based samples. Clinical and hemodynamic stimuli to LV hypertrophy induce not only an increase in cardiac mass and wall thickness but also a fundamental reconfiguration of the protein, cellular and molecular components of the myocardium. Several studies have indicated that LV mass is influenced by genetic factors. The substantial heritability (h(2)) for LV mass in population-based samples of varying ethnicity indicates robust genetic influences on LV hypertrophy. Genome-wide linkage and association studies in diverse populations have been performed to identify genes influencing LV mass, and although several chromosomal regions have been found to be significantly associated with LV mass, the specific genes and functional variants contained in these chromosomal regions have yet to be identified. In addition, multiple studies have tried to link single-nucleotide polymorphisms (SNPs) in regulatory and pathway genes with common forms of LV hypertrophy, but there is little evidence that these genetic variations are functional. Up to this point in time, the results obtained in genetic studies are of limited clinical value. Much of the heritability remains unexplained, the identity of the underlying gene pathways, genes, and functional variants remains unknown, and the promise of genetically-based risk prediction and personalized medicine remain unfulfilled. However, molecular biological technologies continue to improve rapidly, and the long-term potential of sophisticated genetic investigations using these modern genomic technologies, coupled with smart study designs, remains intact. Ultimately, genetic investigations offer much promise for future prevention, early intervention and treatment of this major public health issue.
| S-EPMC3499934 | biostudies-literature
Project description:Determining the etiologies of left ventricular hypertrophy (LVH) can be challenging due to the similarities of the different manifestations in clinical presentation and morphological features. Depending on the underlying cause, not only left ventricular mass but also left ventricular cavity size, or both, may increase. Patients with LVH remain asymptomatic for a few years, but disease progression will lead to the development of systolic or diastolic dysfunction and end-stage heart failure. As hypertrophied cardiac muscle disrupts normal conduction, LVH predisposes to arrhythmias. Distinguishing individuals with treatable causes of LVH is important for prevention of cardiovascular events and mortality. Athletic's heart with physiological LVH does not require treatment. Frequent causes of hypertrophy include etiologies due to pressure/volume overload, such as systemic hypertension, hypertrophic cardiomyopathy, or infiltrative cardiac processes such as amyloidosis, Fabry disease, and sarcoidosis. Hypertension and aortic valve stenosis are the most common causes of LVH. Management of LVH involves lifestyle changes, medications, surgery, and implantable devices. In this review we systematically summarize treatments for the different patterns of cardiac hypertrophy and their impacts on outcomes while informing clinicians on advances in the treatment of LVH due to Fabry disease, cardiac amyloidosis, and hypertrophic cardiomyopathy.
| S-EPMC9135932 | biostudies-literature