Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor

Abstract

Hyperglycemia upregulates intracellular angiotensin II production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than angiotensin receptor blockers (ARBs) or ACE inhibitors. Here we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACE inhibitor. Diabetes was induced in adult mice for 10 wks by streptozotocin. Diabetic mice were treated with insulin, aliskiren (renin inhibitor), benazeprilat (ACE inhibitor), or valsartan (ARB) via subcutaneous minipumps. Significant impairment in diastolic and systolic cardiac function was observed in diabetic mice, which was completely prevented by all three RAS inhibitors. Hyperglycemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, while valsartan was partially effective. Diabetes increased cardiac (pro)renin receptor (PRR) expression and nuclear translocation of promyelocytic zinc finger protein (PLZF), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function as ARBs and ACE inhibitors. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines, and PRR expression suggested subtle differences in their mechanism of action.

Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke

“…For the long-term insulin treatment, insulin (0.7 U/mouse/d, subcutaneously) was administrated daily from third day after the last STZ injection until the mice were sacrificed (Thomas et al, 2013). For the mice treated with insulin only at the onset of reperfusion, continuous administration of intermediate-acting insulin was performed during the 24 h reperfusion.…”

Activation of Foxo1 by Insulin Resistance Promotes Cardiac Dysfunction and β–Myosin Heavy Chain Gene Expression

“…For example, we recently identified angiotensinogen as a Foxo1 target gene, which stimulates angiotensin II generation controlling blood pressure and cellular apoptosis. 12,25 Finally, Foxo1 activation is involved in metabolic remodeling. It has been shown recently that cardiac inactivation of Foxo1 in HFD mice promotes animal survival by protecting cardiac function, 20 in which a major mechanism is that Foxo1 inactivation enhances myocardial glucose utilization via increasing glucokinase gene expression.…”

“…Left ventricular end-diastolic diameter and left ventricular end-systolic diameter were measured from eight 2-dimensional short axis views of M-mode recordings, as we previously described. 9,12 Fractional shortening (FS) was calculated as (left ventricular end-diastolic diameter−left ventricular end-systolic diameter)/left ventricular end-diastolic diameter and expressed as a percentage.…”

“…8 Thus, insulin resistance is recognized as an important mechanism for cardiac dysfunction. 9 The molecular mechanisms of cardiac dysfunction from insulin resistance and diabetes mellitus include increased oxidative stress, altered substrate metabolism, mitochondrial dysfunction, activation of sympathetic nervous activity and the renin angiotensin system, and impaired calcium homeostasis, 3,[10][11][12] but the molecules responsible for insulin action, resistance, and association with cardiac dysfunction are incompletely understood.…”

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

“…Hyperglycaemia has been shown to promote a variety of pathological pathways linked to the development of cardiac abnormalities (Fang et al 2004, Boudina & Abel 2007, Bugger & Abel 2014, Huynh et al 2014. These include the accumulation of advanced glycation end products, altered calcium handling, increased reactive oxygen species (ROS) and activation of the renin-angiotensin system (Fiordaliso et al 2004, Ligeti et al 2006, Goh & Cooper 2008, Yao & Brownlee 2010, Thomas et al 2013. Indeed, a study of almost 50,000 individuals with diabetes demonstrated that, for each 1% increase in glycated haemoglobin, there was an 8% increase in the risk of heart failure (Iribarren et al 2001).…”