A wrinkle in time: circadian biology in pulmonary vascular health and disease.

An often overlooked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery, and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain understudied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, not only including shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently use the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

Association of retinopathy and intima media thickness of common carotid artery in type 2 diabetic patients.

BACKGROUND: This study was carried out in order to evaluate the relationship between retinopathy and carotid intima-media thickness (CIMT). MATERIALS AND METHODS: In a cross-sectional study, 154 diabetic patients who had a history of diabetic disease were evaluated in two equal groups of 77 patients with and without retinopathy, respectively. CIMT was evaluated in all of the patients. RESULTS: Mean age of the patients was 59.65 ± 9.37 years. Mean CIMT of all patients was 0.84 ± 0.18. CIMT of patients with retinopathy was significantly greater than patients without retinopathy (P < 0.001). CIMT also correlated with age, duration of diabetes, systolic blood pressure, blood urea nitrogen, and serum creatinine. CONCLUSION: CIMT may be used as a simple, available and noninvasive method for screening of macro and microvascular complication of diabetic patients.

Defining the age-dependent and tissue-specific circadian transcriptome in male mice.

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

Apparent Absence of BMAL1-Dependent Skeletal Muscle-Kidney Cross Talk in Mice.

BMAL1 is a core mammalian circadian clock transcription factor responsible for the regulation of the expression of thousands of genes. Previously, male skeletal-muscle-specific BMAL1-inducible-knockout (iMS-BMAL1 KO) mice have been described as a model that exhibits an aging-like phenotype with an altered gait, reduced mobility, muscle weakness, and impaired glucose uptake. Given this aging phenotype and that chronic kidney disease is a disease of aging, the goal of this study was to determine if iMS-BMAL1 KO mice exhibit a renal phenotype. Male iMS-BMAL1 KO and control mice were challenged with a low potassium diet for five days. Both genotypes responded appropriately by conserving urinary potassium. The iMS-BMAL1 KO mice excreted less potassium during the rest phase during the normal diet but there was no genotype difference during the active phase. Next, iMS-BMAL1 KO and control mice were used to compare markers of kidney injury and assess renal function before and after a phase advance protocol. Following phase advance, no differences were detected in renal mitochondrial function in iMS-BMAL1 KO mice compared to control mice. Additionally, the glomerular filtration rate and renal morphology were similar between groups in response to phase advance. Disruption of the clock in skeletal muscle tissue activates inflammatory pathways within the kidney of male mice, and there is evidence of this affecting other organs, such as the lungs. However, there were no signs of renal injury or altered function following clock disruption of skeletal muscle under the conditions tested.

Association between common carotid artery intima-media thickness and proteinuria in type 2 diabetic patients.

INTRODUCTION: Proteinuria is the most reliable marker of diabetic nephropathy and an index of atherosclerosis and cardiovascular mortality in diabetic patients. In addition, common carotid artery intima-media thickness (CIMT) is a sensitive marker of early atherosclerosis and cardiovascular risk. The aim of this study was to evaluate the association between proteinuria and CIMT in type 2 diabetic patients. MATERIALS AND METHODS: In a cross-sectional study, 154 patients with type 2 diabetes mellitus were enrolled. The CIMT was measured for all of the patients by one researcher. The 24-hour urine protein was measured using trichloroacetic acid method. RESULTS: A total of 154 type 2 diabetic patients were enrolled with a mean diabetes mellitus duration of 8.91 ± 6.99 years (95 women and 55 men). The mean urinary protein in the patients was 294.70 ± 525.85 mg/24 h. The mean CIMT in all of the patients was 0.84 ± 0.19 mm, and it was greater in the men than in the women (P = .03). The CIMT significantly correlated with patients' age (P < .001), systolic blood pressure (P < .001), and urinary protein excretion (P = .001). There was a marginal positive correlation between diabetes mellitus duration and the CIMT (P = .049). CONCLUSIONS: This study showed a significant association between CIMT, as a sensitive marker of macrovascular complication of diabetes mellitus, and proteinuria as an important index of microvascular complication of the disease.