Long-term administration of angiotensin (1⿿7) prevents heart and lung dysfunction in a mouse model of type 2 diabetes ( db/db ) by reducing oxidative stress, inflammation and pathological remodeling

Abstract

Congestive heart failure is one of the most prevalent and deadly complications of type 2 diabetes that is frequently associated with pulmonary dysfunction. Among many factors that contribute to development and progression of diabetic complications is angiotensin II Ang2). Activation of pathological arm of renin-angiotensin system results in increased levels of Ang2 and signaling through angiotensin type 1 receptor. This pathway is well recognized for its role in induction of oxidative stress (OS), inflammation, hypertrophy and fibrosis. Angiotensin (1-7) [A(1-7)], through activation of Mas receptor, opposes the actions of Ang2 which can result in the amelioration of diabetic complications; enhancing the overall welfare of diabetic patients. In this study, 8 week-old db/db mice were administered A(1-7) daily via subcutaneous injections. After 16 weeks of treatment, echocardiographic assessment of heart function demonstrated significant improvement in cardiac output, stroke volume and shortening fraction in diabetic animals. A(1-7) also prevented cardiomyocyte hypertrophy, apoptosis, lipid accumulation, and decreased diabetes-induced fibrosis and OS in the heart tissue. Treatment with A(1-7) reduced levels of circulating proinflammatory cytokines that contribute to the low grade inflammation observed in diabetes. In addition, lung pathologies associated with type 2 diabetes, including fibrosis and congestion, were decreased with treatment. OS and macrophage infiltration were also reduced in the lungs after treatment with A(1-7). Long-term administration of A(1-7) to db/db mice is effective in improving heart and lung function in db/db mice. Treatment prevented pathological remodeling of the tissues and reduced OS, fibrosis and inflammation.

Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes

“…It remains to be determined whether this is related to a systemic effect on fibrosis formation in patients with diabetes. Pulmonary fibrosis has also been observed in experimental diabetes models [36-38]. Thus, diabetes itself may be associated with a generalized increased risk of fibrosis in several organs.…”

Pulmonary vascular dysfunction in metabolic syndrome

“…; Papinska et al . ), suggesting that inflammation might be occurring in the pulmonary vasculature. Cayir et al .…”

Reduced disease severity following therapeutic treatment with angiotensin 1–7 in a mouse model of multiple sclerosis

“…Assessment of nitrotyrosine expression was performed using immunohistochemistry as described previously by (Papinska et al, 2016). Briefly, 6 µm paraffin-embedded, serial spinal cord tissue sections were treated with Antigen Retrieval Citra solution (Biogenex, California) and were blocked for endogenous avidin, biotin, and non-specific antibody binding for 2 hours with egg white buffer, milk buffer, and 10% goat serum, respectively.…”