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

Pharmacol Res. 2016 May:107:372-380. doi: 10.1016/j.phrs.2016.02.026. Epub 2016 Mar 5.

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.

Keywords: Angiotensin (1-7); Diabetes mellitus; Heart failure; Lung congestion; Remodeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin I / pharmacology
  • Angiotensin I / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use*
  • Apoptosis / drug effects
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use*
  • Cytokines / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Fibrosis
  • Heart / drug effects
  • Heart / physiology
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Lipid Metabolism / drug effects
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Myocardium / metabolism
  • Myocardium / pathology
  • Oxidative Stress / drug effects
  • Peptide Fragments / pharmacology
  • Peptide Fragments / therapeutic use*

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Cardiotonic Agents
  • Cytokines
  • Hypoglycemic Agents
  • Peptide Fragments
  • Angiotensin I
  • angiotensin I (1-7)