Shift work has emerged as a significant health concern in recent years, and research has revealed a link to circadian rhythm dysregulation and atherosclerosis, both of which can increase the risk of cardiovascular disease (CVD). Currently, there is a lack of updated reviews regarding the impact of shiftwork on CVD. Thus, the present narrative review aims to provide a comprehensive summary of the latest research on the relationship between shift work and CVD, identify potential gaps in the current knowledge, and highlight areas for future research. Database searches for peer-reviewed articles published between January 2013 to January 2023 on shift work associated CVD revealed many studies that found shift work is linked with increased prevalence of carotid artery plaque, increased arterial stiffness, and carotid artery intima-media thickness (IMT) all suggestive of a progression of atherosclerosis attributable to shift work. Hypertension, diabetes, and a sedentary lifestyle are known risks for CVD, and the results of the present study suggest that shift work should be added to that list. The elevation of inflammatory markers and DNA damage in shift workers may be linked to their increased progression of atherosclerosis and the positive association of shift work with coronary artery disease. There are minimal studies on mitigating approaches for shift work-related CVD, such as diet modification or exercise, emphasizing the need for further directed research in this area.
BackgroundCalcific aortic valve disease (CAVD) is the pathological remodeling of the valve leaflets which leads to heart failure and high stroke risk. While several mechanisms are known to drive cardiovascular calcification, the initial steps orchestrating the osteogenic reprogramming of cells are not fully understood. Non-canonical functions of telomerase reverse transcriptase (TERT) include service as a cofactor to stimulate gene transcription, and TERT overexpression primes mesenchymal stem cells to differentiate into osteoblasts. We investigated whether TERT contributes to osteogenic reprogramming of valve interstitial cells.MethodsBaseline transcription of TERT and osteogenic markers, senescence, DNA damage, and telomere length in valve tissue and primary aortic valve interstitial cells (VICs) from control and CAVD patients were assessed. TERT expression was depleted in cells using lentiviral vectors. Cells from Tert+/+ and Tert-/- mice were used to validate human findings. Immunofluorescence staining, proximity ligation assay, and chromatin immunoprecipitation assay were used in mechanistic experiments.ResultsTERT protein was highly expressed in calcified valve leaflets, without changes in telomere length, DNA damage, or senescence. These phenotypic features were retained in primary VICs isolated and cultured from those diseased tissues. TERT levels were increased with osteogenic or inflammatory stimuli, and genetic deletion or reduction of TERT prevented calcification of VICs isolated from humans and mice. Similar results were seen in smooth muscle cells (SMCs) and mesenchymal stem cells (MSCs). TERT and Signal Transducer and Activator of Transcription 5A/B (STAT5) colocalize and bind to the Runt-Related Transcription Factor 2 (RUNX2) gene promoter, and TERT and STAT5 co-localized in calcified valve tissues. Pharmacological inhibition of STAT5A prevented calcification in vitro.ConclusionsThese data show that non-canonical TERT activity is required for the calcification of VICs. TERT partners with STAT5A to bind to and activate the RUNX2 gene promoter. These data identify a novel therapeutic target to abate vascular calcification.Novelty and SignificanceWhat Is Known?Calcific aortic valve disease (CAVD) is the most prevalent form of aortic valve pathology. CAVD strongly correlates with age and leads to heart failure and a high risk of stroke. Currently, the only therapeutic option is valve replacement, which comes with significant healthcare costs and additional risks to patients.Runt-related transcription factor 2 (RUNX2) is the master transcription factor required for osteogenic differentiation of osteoblasts and osteogenic reprogramming of vascular cells, yet the early events driving its transcription in valve cells are not well defined.Overexpression of TERT primes mesenchymal stem cells to differentiate down the osteoblast lineage, suggesting that TERT signaling plays an important role in cell differentiation and phenotype.What New Information Does This Article Contribute?TERT protein is highly expressed in calcified aortic leaflets and valve interstitial cells, independent of changes in telomere length.Genetic loss or depletion of TERT blocks calcification in valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells.TERT co-localizes with STAT5 in the cytosol and on the RUNX2 gene promoter, the master regulator of osteogenic transcriptional programs.Pharmacological inhibition of STAT5 prevents calcification of human valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells.What are the clinical implications?We have identified TERT/STAT5 as novel signaling axis that promotes the early transcriptional reprogramming in cardiovascular cells. Inhibiting TERT and STAT5 interaction and activity can be leveraged for the development of pharmacological or biological therapeutic strategies to halt or prevent calcification in the aortic valve and perhaps other cardiovascular tissues.Surgical procedures are currently the only treatment option for patients with CAVD. Discovering the early events driving vascular calcification identifies novel and druggable targets for the development of non-surgical therapies.
Arterial Calcification due to Deficiency of CD73 (ACDC) is a rare genetic disease caused by a loss-of-function mutation in the NT5E gene encoding the ecto-5′-nucleotidase (cluster of differentiation 73, CD73) enzyme. ACDC patients develop vessel arteriomegaly, tortuosity, and vascular calcification in their lower extremity arteries. Histological analysis shows that ACDC patient vessels exhibit fragmented elastin fibers similar to that seen in aneurysmal-like pathologies. It is known that alterations in transforming growth factor β (TGFβ) pathway signaling contribute to this elastin phenotype in several connective tissue diseases, as TGFβ regulates extracellular matrix (ECM) remodeling. Our study investigates whether CD73-derived adenosine modifies TGFβ signaling in vascular smooth muscle cells (SMCs). We show that Nt5e−/− SMCs have elevated contractile markers and elastin gene expression compared to Nt5e+/+ SMCs. Nt5e-deficient SMCs exhibit increased TGFβ-2 and activation of SMAD signaling, elevated elastin transcript and protein, and potentiates SMC contraction. These effects were diminished when the A2b adenosine receptor was activated. Our results identify a novel link between adenosine and TGFβ signaling, where adenosine signaling via the A2b adenosine receptor attenuates TGFβ signaling to regulate SMC homeostasis. We discuss how disruption in adenosine signaling is implicated in ACDC vessel tortuosity and could potentially contribute to other aneurysmal pathogenesis.
Cardiovascular calcification is a highly prevalent pathological process found in the vessels and valves in the elderly and patients with diabetes, hypertension, and renal disease. Calcific aortic valve disease (CAVD) stiffens and remodels the valve leaflets and leads to valve dysfunction, cardiac failure, and increased stroke risk. Vascular calcification can occur in the necrotic core of atherosclerotic plaques or in the medial layer of arteries. However, the initial steps dictating the onset of calcification remain ill-defined. Multiple studies have revealed that the protein telomerase reverse transcriptase (TERT), the catalytic subunit of the enzymatic complex required for telomere length maintenance, is a co-factor to stimulate gene transcription, and its overexpression primes mesenchymal stem cells to differentiate into osteoblasts. We determined that TERT is required for the calcification valve interstitial cells (VICs) and coronary smooth muscle cells (SMCs); TERT expression and protein are increased in calcified tissues and cell lines, independent of changes in telomere length. Genetic deletion of Tert in murine VICs and SMCs prevented calcification. Upon osteogenic stimulation, TERT binds to Signal Transducer and Activator of Transcription 5A/B (STAT5) to translocate into the nucleus where the complex binds to the RUNX2 promoter to induce expression. We found that VICs cultured under inflammatory conditions calcified and upregulated STAT5, suggesting that inflammatory signaling may promote calcification in VICs. Lastly, testing several STAT5 inhibitors, we determined that STAT5A is required for the calcification of VICs and SMCs. These findings are the first to suggest that TERT and STAT5 are involved in driving the osteogenic switch and calcification of vascular cells and constitute potential therapeutic targets for the treatment of CAVD.
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