Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Abstract

Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis.

Speckle-tracking echocardiography combined with imaging mass spectrometry assesses region-dependent alterations

“…In accordance with previous studies 23 , mice suffering from type 1 diabetes mellitus displayed increases in blood glucose levels at 6w, 9w, and 12w after STZ application versus corresponding controls, respectively (Fig. 1a).…”

“…Interestingly, we observed less collagen I at 12w post-STZ compared to 9w STZ, paralleled by lower Lox and LoxL2 levels, as markers for collagen cross-linking 36 . The reduction in collagen at 12w STZ www.nature.com/scientificreports www.nature.com/scientificreports/ per se is contradictory to already published studies, reporting higher collagen levels 3,23,31 . Only one study, investigating the effect of thioredoxin-interacting protein, reported less myocardial collagen at 16w STZ compared to controls 37 .…”

Evodiamine Attenuates P2X7‐Mediated Inflammatory Injury of Human Umbilical Vein Endothelial Cells Exposed to High Free Fatty Acids

“…However, NO-mediated vascular relaxation was damaged in insulin resistance and diabetes, suggesting endothelium dysfunction [29]. Furthermore, endothelial cell injury and dysfunction are associated with upregulation of oxidative stress.…”

Quantification of Relaxin-2 Connecting Peptide (Pro-RLX2) in Human Blood Samples

“…However, none of these assay methods have published details regarding sensitivity and reliability. Nevertheless, some of them have been successfully used for clinical studies with different questions, e.g., birthweight regulation and other pregnancy complications (17,18,30), peripartum cardiomyopathy (31), vascular dysfunction in type 1 diabetes (32), and cirrhosis (33).…”