The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin‐converting enzyme (ACE) comprises the classical RAS. The non‐classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1‐7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non‐classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

Since the beginning of time people explored and developed new technologies to make their activities of daily living less labour intense, more efficient and, consequently, more sedentary. In addition, technological advances in medicine throughout history have led to a substantial increase in life expectancy. However, the combination of increased sedentary behaviour and increased life-expectancy resulted in a sharp increase in overweight and obesity related chronic conditions and illness. Although people may live longer, they are doing so with poorer physical function and a reduced quality of life. In this review we explore how technological advances have influenced people's sedentary behaviour and, through the lens of the affective-reflective theory (ART), we propose a means by which technology could be repurposed to encourage greater engagement in physical activity.

There is increasing evidence for the involvement of the skeleton in the regulation of atherosclerotic vascular disease. Osteocalcin, an osteoblast derived protein, exists in two forms, carboxylated and undercarboxylated osteocalcin. Undercarboxylated osteocalcin has been linked to the regulation of metabolic functions, including glucose and lipid metabolism. Features of atherosclerosis have been associated with circulating osteocalcin; however, this association is often conflicting and unclear. Therefore, the aim of this review is to examine the evidence for a role of osteocalcin in atherosclerosis development and progression, and in particular endothelial dysfunction and vascular calcification. The current literature suggests that undercarboxylated osteocalcin stimulates the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway to upregulate nitric oxide and nuclear factor kappa β (NF-кβ) in vascular cells, possibly protecting endothelial function and preventing atherogenesis. However, this effect may be mediated by metabolic factors, such as improvements in insulin signaling, rather than through a direct effect on the vasculature. Total osteocalcin is frequently associated with vascular calcification, an association that may occur as a result of vascular cells eliciting an osteogenic phenotype. Whether osteocalcin acts as a mediator or a marker of vascular calcification is currently unclear. As such, further studies that examine each form of osteocalcin are required to elucidate if it is a mediator of atherogenesis, and whether it functions independently of metabolic factors.

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Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

Background The bone-derived protein osteocalcin (OC), in its undercarboxylated (ucOC) form, has a beneficial effect on energy metabolism and may be a future therapeutic target for metabolic diseases. Increasing evidence suggests a link between ucOC and cardiovascular disease (CVD) development; however, the exact relationship is conflicting and unclear. Scope of review The aim of this review was to summarise the current research examining the interaction between OC and vascular dysfunction, the initiating stage in the development of atherosclerosis and CVD. Major conclusions In humans, the association between OC and vascular function is inconsistent. Several studies report that total OC (tOC) is associated with adverse function or beneficial function, whereas others report that tOC and ucOC has no effect on vascular function. The conflicting data are likely due to several methodological inconsistencies, in particular the lack of studies reporting circulating ucOC levels. In animal models, the direct administration of ucOC to isolated blood vessels ex vivo produced minimal changes in endothelial function, but importantly, no adverse responses. Finally, in human endothelial and vascular smooth muscle cells, ucOC treatment did not influence classical markers of cellular function, including endothelin-1, vascular adhesion molecule-1 and monocyte chemoattractant protein-1 after exposure to high glucose and inflammatory conditions. The lack of adverse effects in ex vivo and in vitro studies suggests that ucOC may be targeted as a future therapeutic for metabolic diseases, without the risk of detrimental effects in the vasculature. However, further studies are needed to confirm these findings and to investigate whether there is a direct beneficial influence of ucOC.

Background There are conflicting reports on the association of undercarboxylated osteocalcin (ucOC) in cardiovascular disease development, including endothelial function and hypertension. We tested whether ucOC is related to blood pressure and endothelial function in older adults, and if ucOC directly affects endothelial-mediated vasodilation in the carotid artery of rabbits. Methods In older adults, ucOC, blood pressure, pulse wave velocity (PWV) and brachial artery flow-mediated dilation (BAFMD) were measured (n = 38, 26 post-menopausal women and 12 men, mean age 73 ± 0.96). The vasoactivity of the carotid artery was assessed in male New Zealand White rabbits following a four-week normal or atherogenic diet using perfusion myography. An ucOC dose response curve (0.3–45 ng/ml) was generated following incubation of the arteries for 2-hours in either normal or high glucose conditions. Results ucOC levels were higher in normotensive older adults compared to those with stage 2 hypertension (p < 0.05), particularly in women (p < 0.01). In all participants, higher ucOC was associated with lower PWV (p < 0.05), but not BAFMD (p > 0.05). In rabbits, ucOC at any dose did not alter vasoactivity of the carotid artery, either following a normal or an atherogenic diet (p > 0.05). Conclusion Increased ucOC is associated with lower blood pressure and increased arterial stiffness, particularly in post-menopausal women. However, ucOC administration has no direct short-term effect on endothelial function in rabbit arteries. Future studies should explore whether treatment with ucOC, in vivo, has direct or indirect effects on blood vessel function.