👤 Guadalupe Villarreal

The apolipoprotein E (APOE) ε4 allele represents the strongest genetic risk factor for Alzheimer's disease (AD), but its role in genetically diverse Latin American and Caribbean (LAC) populations is underexplored. We conducted a meta-analysis of 35 studies from 11 LAC countries, encompassing 3206 patients with AD and 5515 controls. The ε4 allele demonstrated significant association with increased AD risk (odds ratio [OR] = 3.25, 95% confidence interval [2.82-3.76]), while ε3 showed lower odds (0.42, [0.37-0.48]). Homozygous ε4/ε4 carriers had elevated risk (6.84, [5.09-9.19]), and heterozygous ε3/ε4 carriers showed moderate risk (2.59, [2.31-2.91]). Country-level analyses revealed variability, with Ecuador showing the highest OR for ε4/ε4 (13.29, [1.56-113.4]). These results confirm APOE ε4 as a major AD risk factor in LAC populations and highlight regional differences relevant to precision medicine. Show less

The Kruppel-like factor 2 (KLF2) and Kruppel-like factor 4 (KLF4) transcription factors have recently been shown to act as critical regulators of endothelial homeostasis. While several insights have been made into the signaling mechanisms orchestrating endothelial KLF2 expression, those governing the expression of KLF4 in the vascular endothelium remain largely unknown. Here, we show that diverse vasoprotective stimuli including an atheroprotective shear stress waveform, simvastatin, and resveratrol induce the expression of KLF4 in cultured human endothelial cells. We further demonstrate that the induction of KLF4 by resveratrol and atheroprotective shear stress occurs via a MEK5/MEF2-dependent signaling pathway. Since MEK5 activation is also critical for the expression of KLF2, we assessed the individual contribution of KLF4 and KLF2 to the global transcriptional activity triggered by MEK5 activation. Genome-wide transcriptional profiling of endothelial cells overexpressing KLF4, KLF2, or constitutively active MEK5 revealed that 59.2% of the genes regulated by the activation of MEK5 were similarly controlled by either KLF2 or KLF4. Collectively, our data identify a significant degree of mechanistic and functional conservation between KLF2 and KLF4, and importantly, provide further insights into the complex regulatory networks governing endothelial vasoprotection. Show less

Resveratrol activates Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase which modulates metabolic homeostasis and improves several pathophysiological features present in diseases of ageing. In particular, it has been shown that SIRT1 activation improves endothelial dysfunction and suppresses vascular inflammation, two central pathophysiological processes involved in the initiation and progression of cardiovascular disease. The downstream targets of SIRT1 activation in this context, however, remain poorly defined. Therefore, in this study, we aimed to characterize mechanistically how SIRT1 activation regulates the endothelial vasoprotective phenotype. We demonstrate that SIRT1 activation by resveratrol increases the expression of the transcription factor Krüppel-like factor 2 (KLF2) in human vascular endothelial cells, resulting in the orchestrated regulation of transcriptional programs critical for conferring an endothelial vasoprotective phenotype. Moreover, we show that KLF2 upregulation by resveratrol occurs via a mitogen-activated protein kinase 5/myocyte enhancing factor 2-dependent signalling pathway. Collectively, these observations provide a new mechanistic framework to understand the vascular protective effects mediated by SIRT1 activators and define KLF2 as a critical mediator of these effects. Show less