Cardiac-targeted delivery of nuclear receptor RORα via ultrasound targeted microbubble destruction optimizes the benefits of regular dose of melatonin on sepsis-induced cardiomyopathy

Abstract

Background Large-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy. Methods Melatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16–20 h after inducing fatal sepsis. Results We observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague–Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation. Conclusions These findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.

Anemonin inhibits sepsis‐induced acute kidney injury via mitigating inflammation and oxidative stress

“…Lower serum melatonin has been found in septic patients. 30 In adult patients with severe coronavirus infection (COVID-19), melatonin addition significantly (p < 0.05) improved thrombosis and sepsis development and reduced mortality. 31 Moreover, dexmedetomidine protects against septic liver injury 32 and also relieves LPS-induced AKI 33 through the AMPK signaling pathway.…”

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

“…no. 700001P-200MG-B-021, Avanti Polar Lipids, Inc.), was prepared and processed to form a thin lipid film (mass ratio, 5:2:0.5) ( 10 ). Glycerol solution (cat.…”

“…The CMBs were diluted to 1×10 9 /ml with PBS (C0221A, Beyotime Institute of Biotechnology), treated with 60 Co-γ irradiation (BFT-II Cobalt-60 gamma-ray Irradiation Device, MDS Nordion) and stored at 4°C. The particle size distribution and surface potential were determined using the Zetasizer Nano ZS system (Malvern Panalytical Ltd.) ( 10 ).…”

“…Ultrasound-targeted microbubble destruction (UTMD) is an emerging approach for targeted delivery of drugs and gene transport to specific tissues ( 10 ). Employing low-frequency ultrasound offers the advantages of enhanced penetration, reduced attenuation and focalization on deep-seated local tissues ( 11 ).…”

“…Intravenous microbubbles flow in the bloodstream and oscillate, collapsing within the target tissue under ultrasound stimulation, causing localized cavitation effects that enhance the penetration and uptake of carried plasmids ( 12 ). The UTMD technique has demonstrated efficacy and safety in gene delivery to target organs and is extensively validated in rodent and primate models ( 10 ). Furthermore, UTMD circumvents ethical and biosafety controversies associated with viral gene delivery ( 13 ), and the clinical safety of ultrasound microbubbles is widely recognized in diagnostics and therapy ( 14 , 15 ).…”