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Abstract Background Although diabetic patients have an increased rate of cardio-vascular events, there is considerable heterogeneity with respect to cardiovascular risk, requiring new approaches to individual cardiovascular risk factor assessment. In this study we used whole body-MR-angiography (WB-MRA) to assess the degree of atherosclerosis in patients with long-standing diabetes and to determine the association between metabolic syndrome (MetS) and atherosclerotic burden. Methods Long standing (≥10 years) type 1 and type 2 diabetic patients (n = 59; 31 males; 63.3 ± 1.7 years) were examined by WB-MRA. Based on the findings in each vessel, we developed an overall score representing the patient's vascular atherosclerotic burden (MRI-score). The score's association with components of the MetS was assessed. Results The median MRI-score was 1.18 [range: 1.00-2.41] and MetS was present in 58% of the cohort (type 2 diabetics: 73%; type 1 diabetics: 26%). Age (p = 0.0002), HDL-cholesterol (p = 0.016), hypertension (p = 0.0008), nephropathy (p = 0.0093), CHD (p = 0.001) and MetS (p = 0.0011) were significantly associated with the score. Adjusted for age and sex, the score was significantly (p = 0.02) higher in diabetics with MetS (1.450 [1.328-1.572]) compared to those without MetS (1.108 [0.966-1.50]). The number of MetS components was associated with a linear increase in the MRI-score (increase in score: 0.09/MetS component; r2 = 0.24, p = 0.038). Finally, using an established risk algorithm, we found a significant association between MRI-score and 10-year risk for CHD, fatal CHD and stroke. Conclusion In this high-risk diabetic population, WB-MRA revealed large heterogeneity in the degree of systemic atherosclerosis. Presence and number of traits of the MetS are associated with the extent of atherosclerotic burden. These results support the perspective that diabetic patients are a heterogeneous population with increased but varying prevalence of atherosclerosis and risk.

Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. J. Cell. Physiol. 231: 1276-1282, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article examines the role of the orphan nuclear receptor NOR1 in the development of atherosclerosis. According to the authors, NOR1 positively regulates monocyte recruitment to the vascular wall, thereby performing an atherogenic role. The authors were also able to identify a pathway underlying monocyte adhesion which explains how the nuclear receptor affects the process of atherosclerosis development.

Background: Although diabetic patients have an increased rate of cardio-vascular events, there is considerable heterogeneity with respect to cardiovascular risk, requiring new approaches to individual cardiovascular risk factor assessment. In this study we used whole body-MR-angiography (WB-MRA) to assess the degree of atherosclerosis in patients with long-standing diabetes and to determine the association between metabolic syndrome (MetS) and atherosclerotic burden. Methods: Long standing (≥10 years) type 1 and type 2 diabetic patients (n = 59; 31 males; 63.3 ± 1.7 years) were examined by WB-MRA. Based on the findings in each vessel, we developed an overall score representing the patient's vascular atherosclerotic burden (MRI-score). The score's association with components of the MetS was assessed. Results: The median MRI-score was 1.18 [range: 1.00-2.41] and MetS was present in 58% of the cohort (type 2 diabetics: 73%; type 1 diabetics: 26%). Age (p = 0.0002), HDL-cholesterol (p = 0.016), hypertension (p = 0.0008), nephropathy (p = 0.0093), CHD (p = 0.001) and MetS (p = 0.0011) were significantly associated with the score. Adjusted for age and sex, the score was significantly (p = 0.02) higher in diabetics with MetS (1.450 [1.328-1.572]) compared to those without MetS (1.108 [0.966-1.50]). The number of MetS components was associated with a linear increase in the MRI-score (increase in score: 0.09/MetS component; r² = 0.24, p = 0.038). Finally, using an established risk algorithm, we found a significant association between MRI-score and 10-year risk for CHD, fatal CHD and stroke. Conclusion: In this high-risk diabetic population, WB-MRA revealed large heterogeneity in the degree of systemic atherosclerosis. Presence and number of traits of the MetS are associated with the extent of atherosclerotic burden. These results support the perspective that diabetic patients are a heterogeneous population with increased but varying prevalence of atherosclerosis and risk. [ABSTRACT FROM AUTHOR]

The article presents a discussion concerning the inhibition of vascular smooth muscle cell (VSMC) proliferation on peroxisome proliferation-activated receptor (PPAR)α/p16INK4a pathway by repressing cell cycle-dependent telomerase activation. It also demonstrates that PPARα's antiproliferative effects in VSMCs depend on the suppression of tolemerase activity by targeting the p16/RB/E2F transcriptional cascade.

Background: Vascular disease, including coronary heart disease (CAD), peripheral vascular disease and cerebrovascular disease, is the major cause of morbidity and death in diabetes. A recently introduced MRI technique was used to obtain an extensive assessment (excluding coronaries) of the vascular status in 65 diabetic patients. Methods: Long-standing ≥10 years) type 1 (n=20) or type 2 (n=45) diabetic patients (35 males, 63±13.1 years) were examined on a 1.5 Tesla or 3.0 Tesla whole body MRI. Cerebral arteries, abdominal aorta, and arteries of the upper and lower extremities (including pedal arteries) were imaged in one session (MR angiogram). Atherosclerotic lesions were quantified in each vessel (6 levels ranging from normal to occlusion) and the sum divided by the number of vessels evaluated resulted in an overall score, representing the patient's vascular status. The score's association with clinical and biochemical parameters was assessed with a generalized linear model (age and sex adjusted; SAS 9.1). Results: Age (p=0.0008) and male sex (p=0.029) were significantly associated with the score (r²=0.23). Adjusted for age and sex, the score was also associated with CAD status (r²=0.32; p=0.005), retinopathy (r²=0.31; p=0.007), serum creatinine (r²=0.34; p=0.006) and somewhat with diabetes duration (r²=0.26; p=0.07). BMI, blood pressure, smoking, type of diabetes, HbA1c, LDL-concentration and medications were not associated with the score. Conclusion: Our MRI based score evaluating vascular pathology (without coronaries) is significantly associated with CAD status, indicating that atherosclerosis has a similar etiology in coronary, cerebral and peripheral arteries in diabetes. Age, male sex, retinopathy, nephropathy (and perhaps duration of diabetes) are important predictors of an elevated score, indicating high atherosclerotic burden. BMI, blood pressure, HbA1c, LDL, and medications were not important predictors (probably because single on-treatment measurements were used). Whole-body MRI is a promising method for comprehensive atherosclerotic evaluation in diabetes. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor (PPAR)alpha, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARalpha activation suppresses G(1)-->S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16(INK4a) (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARalpha is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARalpha activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect that was dependent on p16. The inhibition of cell proliferation by PPARalpha activation was lost in VSMCs following TERT overexpression or knockdown, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARalpha. Finally, we demonstrate that PPARalpha agonists suppress telomerase activation during the proliferative response following vascular injury, indicating that these findings are applicable in vivo. In concert, these results demonstrate that the antiproliferative effects of PPARalpha in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade.