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

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

Novel AT2R agonist, β-Pro7Ang III, is cardio- and vaso-protective in diabetic spontaneously hypertensive rats

Stimulation of the angiotensin II type 2 receptor (AT2R) evokes protective effects in various cardiovascular diseases. Thus, this study aimed to investigate the effects of AT2R stimulation, with or without AT1R blockade, in a model of hypertension with concomitant type 1 diabetes mellitus (T1DM). Spontaneously hypertensive rats (SHRs) were given either citrate or a single dose of streptozotocin (STZ; 55 mg/kg, i.p.) to induce diabetes. After 4 weeks of diabetes, animals were administered either a vehicle (saline), AT2R agonist, β-Pro7Ang III (0.1 mg/kg/day via osmotic mini-pump), AT1R blocker, candesartan (2 mg/kg/day via drinking water), or a combination of both for a further 8 weeks. β-Pro7Ang III treatment had no effect on blood pressure, but attenuated the significant increase in cardiac interstitial collagen and protein expression of fibrotic and inflammatory markers, and superoxide levels that was evident in diabetic SHRs. These effects were not observed with candesartan, despite its blood pressure lowering effects. Although β-Pro7Ang III had no effect on aortic fibrosis, it significantly attenuated MCP-1 protein expression and superoxide levels when compared to both the non-diabetic and diabetic SHRs, to a similar extent as candesartan. In both the heart and vasculature, the effects of β-Pro7Ang III in combination with candesartan were similar to those of β-Pro7Ang III alone, and superior to candesartan alone. It was concluded that in hypertension with concomitant diabetes, AT2R stimulation with a novel ligand alone, or in combination with AT1R blockade, improved the cardiac and vascular structural changes that were strongly associated with inflammation and oxidative stress, independent of blood pressure regulation