Activation of the GLP-1 Receptor by Liraglutide Increases ACE2 Expression, Reversing Right Ventricle Hypertrophy, and Improving the Production of SP-A and SP-B in the Lungs of Type 1 Diabetes Rats

Abstract

Diabetes alters microvascular function in the vascular beds of organs, including the lungs. Cardiovascular complications of pulmonary vascular affectation may be a consequence of the overactivation of the vasoconstrictive and proliferative components of the renin-angiotensin system. We previously reported that pulmonary physiology and surfactant production is improved by the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide (LIR) in a rat model of lung hypoplasia. Because we hypothesized that streptozotocin-induced diabetes rats would show deficiencies in lung function, including surfactant proteins, and develop an imbalance of the renin-angiotensin system in the lungs. This effect would in turn be prevented by long-acting agonists of the GLP-1R, such as LIR. The induction of diabetes reduced the surfactant protein A and B in the lungs and caused the vasoconstrictor component of the renin-angiotensin system to predominate, which in turn increased angiotensin II levels, and ultimately being associated with right ventricle hypertrophy. LIR restored surfactant protein levels and reversed the imbalance in the renin-angiotensin system in this type 1 diabetes mellitus rat model. Moreover, LIR provoked a strong increase in angiotensin-converting enzyme 2 expression in the lungs of both diabetic and control rats, and in the circulating angiotensin(1-7) in diabetic animals. These effects prompted complete reversion of right ventricle hypertrophy. The consequences of LIR administration were independent of glycemic control and of glucocorticoids, and they involved NK2 homeobox 1 signaling. This study demonstrates by first time that GLP-1R agonists, such as LIR, might improve the cardiopulmonary complications associated with diabetes.

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression

“…[42] Among other diabetic medications, the use of liraglutide and pioglitazone have also been found to be related with increased ACE2 regulation in animal studies. [42,43] The interconnection between ACE2, renin-angiotensin system (RAS) signalling, aging, DM, hypertension, and severity of COVID-19 may not be as simple as it may seem. As we described before, our meta-regression analysis showed that the association between DM and poor outcome was interdependent on age and hypertension.…”

Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways

“…Study shows that activation of pulmonary ACE2 enzyme by a small synthetic molecule XNT (1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[[(4-methylphenyl)sulfonyl]oxy]-9H-xanthene-9-one) prevents pulmonary hypertension and vascular remodeling, and suggests that pulmonary ACE2 may be a novel target for the successful control of pulmonary hypertension16. In addition of some studies showed activation of GLP-1 receptor by liraglutide increases ACE2 expression and preservation of GLP-1 is associated with a reduction of angiotensin II-induced cardiac fibrosis, and reversing right ventricular hypertrophy in type 1 diabetes rats2829. We conclude that liraglutide has a great potential as an anti-pulmonary hypertension drug.…”

Diabetes and COVID-19: evidence, current status and unanswered research questions

“…However, propensity of thiazolidinediones to cause fluid retention and the risk of congestive heart failure in COVID-19 would make these agents unfavourable for treatment. Glucagon-like peptide-1 agonists have has been shown to increase ACE2 and increase surfactant in experimental animals [18]. Practical significance of changes in ACE2 levels with use of thiazolidinediones and glucagon-like peptide-1 agonists is not known.…”