Myocardial delivery of a mitochondria-targeted H2S donor restores bioenergetics and cardiac performance in diabetic cardiomyopathy
Y Yang, Z Xu, M Qian, F Gao, Z Qiang, W ZhijianAbstract
Background
Diabetic cardiomyopathy (DCM) is a major substrate for heart failure in diabetes and remains without effective therapies to halt its progression. Mitochondrial dysfunction and impaired myocardial bioenergetics are increasingly recognised as key contributors to DCM pathogenesis. Hydrogen sulfide (H₂S) is an endogenous cardioprotective mediator with mitochondrial actions, but translation is constrained by limited cardiac exposure and off-target effects after systemic administration.
Purpose
To determine whether myocardial delivery of a mitochondria-targeted H₂S donor improves cardiac function and remodelling in DCM models.
Methods
Type 2 diabetes was modelled in leptin receptor–deficient db/db mice and in high-fat diet plus streptozotocin–induced mice. AP39 was formulated in a DSPE-PEG–based lipid nanocarrier and the surface was decorated with a cardiac-targeting peptide to yield CTP–AP39–DSPE-PEG. Comparators included non-targeted AP39–DSPE-PEG, vehicle DSPE-PEG carrier, and NaHS as a widely used fast-releasing sulfide donor. Cardiac function was assessed by echocardiography. Myocardial remodelling and mitochondrial morphology were evaluated by histology and electron microscopy. Mitochondrial bioenergetics and oxidative stress were assessed using biochemical assays and Seahorse respiration profiling. Integrated transcriptomics and proteomics with immunoblotting were used for mechanistic interrogation.
Results
Physicochemical characterisation demonstrated colloidal stability and reproducible AP39 encapsulation. In vivo and ex vivo imaging confirmed enhanced cardiac accumulation and prolonged myocardial retention after cardiac-targeting peptide decoration. Across both diabetic models, the targeted formulation improved left ventricular systolic and diastolic function and attenuated hypertrophy, fibrosis and lipid deposition. Mitochondrial structural damage was reduced, accompanied by improved respiratory capacity on Seahorse profiling, restoration of myocardial bioenergetic capacity and reduced mitochondrial oxidative stress. Benefits exceeded those achieved with non-targeted AP39–DSPE-PEG, whereas functional improvement was limited with NaHS. Integrated proteomics and transcriptomics showed a shift towards a non-diabetic-like molecular profile, with differential molecules enriched in mitochondrial and endoplasmic reticulum compartments and processes governing energy metabolism and Ca²⁺ homeostasis. These findings implicated signalling at the ER–mitochondria interface and were supported by immunoblot modulation of the ITPR3–GRP75–VDAC1 axis.
Conclusions
These findings suggest that myocardial targeting of a mitochondria-directed H₂S donor may represent a potential therapeutic approach for DCM by improving cardiac performance and remodelling and restoring mitochondrial bioenergetics.Fig 1Targeting Imaging Echo TEMFig 2Bioenergetics Seahorse GO WB