Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.
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http://dx.doi.org/10.1172/JCI96477 | DOI Listing |
PLoS One
January 2025
Department of Vascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Background: The impact of moderate-to-vigorous physical activity (MVPA) on all-cause mortality in type 2 diabetes (T2D) patients with severe abdominal aortic calcification (SAAC) remains unclear.
Methods: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014, including T2D patients aged 40 years and older. AAC was assessed using the Kauppila scoring system, with SAAC defined as a score >6.
Cardiovasc Res
December 2024
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Aim: Microcalcification increases the vulnerability of plaques and has become an important driver of acute cardiovascular events in diabetic patients. However, the regulatory mechanisms remain unclear. DJ-1, a multifunctional protein, may play a potential role in the development of diabetic complications.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Erasmus University Medical Center, Rotterdam, Netherlands.
Background: Increasing evidence shows a link between arterial calcification in the heart-brain axis and cognitive performance. However, how calcification relates to acceleration of cognitive changes, and which specific cognitive domains are mostly affected, remains unclear. We assessed the impact of calcification in major arteries between the heart and brain on cognitive decline and focused on different cognitive domains.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Background: Vascular disorders are proposed as modifiable risk factors for dementia; yet, physiologic mechanisms connecting vascular disorders to cognitive impairment remain unknown. We examined subclinical cardiovascular measures to determine which predict global cognitive decline and domain specific cognitive impairment and point to potential pathways linking subclinical vascular disease and dementia.
Methods: MESA includes a diverse cohort of 6,814 participants free from clinical cardiovascular disease with follow-up over 6 clinical examinations and annual follow-up calls.
Alzheimers Dement
December 2024
Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Background: Vascular risk factors captured in midlife represent modifiable features of cardiovascular disease (CVD), stroke, dementia, and dementia-related neuropathology. Subclinical measures of CVD may help identify specific structural and function aspects underlying vascular contributions to cognitive impairment and dementia over and above conventional dementia risk scores.
Method: The MESA study followed a diverse cohort of 6,814 adults aged 45-84 years over 6 clinical examinations and annual follow-up calls since baseline, 2000-2002.
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