Ultrasound-targeted microbubble destruction technology delivering -klotho to the heart enhances FGF21 sensitivity and attenuates heart remodeling post-myocardial infarction

Fibroblast growth factor (FGF)21 is a peptide hormone that improves mitochondrial function and energy metabolism, and the deficiency of its co-receptor beta-klotho (KLB) causes decreased FGF21 sensitivity. The present study examined whether the cardiac delivery of plasmids containing the KLB gene via ultrasound-targeted microbubble destruction (UTMD) enhances the efficacy of FGF21 against heart failure post-acute myocardial infarction (AMI). For this purpose, the levels of FGF21 in patients and rats with heart dysfunction post-infarction were determined using ELISA. Sprague-Dawley rats received the 3X UTMD-mediated delivery of KLB@cationic microbubbles (KLB@CMBs) 1 week following the induction of AMI. Echocardiography, histopathology and biochemical analysis were performed at 4 weeks following the induction of AMI. The results revealed that patients with heart failure post-infarction had higher serum FGF21 levels than the healthy controls. However, the downstream signal, KLB, but not alpha-klotho, was reduced in the heart tissues of rats with AMI. As was expected, treatment with FGF21 did not substantially attenuate heart remodeling post-infarction. It was found that decreased receptors KLB in the heart may result in the insensitivity to FGF21 treatment. In vivo, the UTMD technology-mediated delivery of KLB@ CMBs to the heart significantly enhanced the effects of FGF21 administration on cardiac remodeling and mitochondrial dysfunction in the rats following infarction. The delivery of KLB to the heart by UTMD and the administration of FGF21 attenuated mitochondrial impairment and oxidative stress by activating nuclear factor erythroid 2-related factor 2 signals. On the whole, the present study demonstrates that the cardiac delivery of KLB significantly optimizes the cardioprotective effects of FGF21 therapy on adverse heart remodeling. UTMD appears a promising interdisciplinary approach with which to improve heart failure post-myocardial infarction.