Cardiovascular and brain effects of liraglutide in transthyretin amyloidosis (ATTR) mice models.

Abstract

Aim: The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in hereditary transthyretin amyloidosis (ATTRv) remain uncertain. This study aims to investigate whether liraglutide interacts with transthyretin protein (TTR) and thereby exerts therapeutic effects for ATTRv. Methods: High throughput screening was conducted to characterize the drug targets of liraglutide, and microscale thermophoresis was used to observe direct binding of liraglutide to TTR. Humanized RBP4/TTR (normal)and RBP4/TTR^Val50Met (ATTRv) mice were constructed, and treated with liraglutide (0.3mg/kg/d) or placebo for 28 days. Fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), and plasma brain natriuretic peptide (BNP) were measured. Brain and cardiac tissues were processed with western blot, enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (PCR), and pathological staining to evaluate the lesion status in corresponding organs. Results: Liraglutide exhibited high affinity and direct combination ability to TTR. In ATTRv mice, liraglutide significantly decreased the contents of TTR protein in brain compared with placebo. However, the cardiovascular prognosis measurements including heart failure (plasma BNP concentrations), cardiac fibrosis (the relative expression levels of Cola1 and TGFβ1 in cardiac tissues), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between mice receiving liraglutide and placebo treatment. Conclusion: Liraglutide could decrease the deposition of TTR in brain tissues, while it did not improve cardiovascular outcomes in ATTRv mice compared to placebo. More researches regarding the mechanisms and therapeutic effects of GLP-1RAs to ATTRv are still required.