Mechano-matching hydrogel patch promotes myocardial infarction repair via YAP-Bcl-2 pathway activation

Although elastic cardiac patches have demonstrated efficacy in alleviating ventricular wall stress and restoring cardiac function following myocardial infarction (MI), the mechanistic basis governing their therapeutic effects remains incompletely elucidated. In this study, three distinct acellular hydrogel patches with tailored elastic moduli were fabricated, namely soft (1.61 kPa), mechano-matching (16.82 kPa, corresponding to the moduli of native adult myocardium), and rigid (602.61 kPa). These patches were implanted in a rat model of MI to evaluate their therapeutic potential. Among the three groups, the mechano-matching hydrogel patch exhibited superior performance, significantly improving cardiac function (with left ventricular ejection fraction [LVEF] elevated by 15.89 %, <i>p</i> = <i>0.002</i>), reducing infarct size by 14.49 % (<i>p</i> < <i>0.001</i>), mitigating myocardial fibrosis, and attenuating cardiomyocyte apoptosis. To dissect the underlying mechanism, an in vitro cyclic stretch model mimicking the in vivo myocardial mechanical microenvironment was established. Results revealed that hydrogels with moderate stiffness (16.82 kPa) transduced mechanical cues to promote nuclear translocation of Yes-associated protein (YAP) in cardiomyocytes. This key mechanotransduction event upregulated the expression of anti-apoptotic protein Bcl-2, thereby suppressing cardiomyocyte apoptosis. Notably, this study uncovers a previously unelucidated mechanistic paradigm by which moderate mechanical stimuli, matching the intrinsic stiffness of native myocardium, confer cardioprotection specifically through activation of the YAP-Bcl-2 signaling axis. Furthermore, it establishes that acellular biomaterials can exclusively harness their intrinsic mechanical properties to reverse pathological myocardial remodeling post-MI, without relying on cellular components or bioactive molecules. This finding provides strategy guided by mechanobiology for cardiac regeneration, substantially enhancing the clinical translatability of acellular cardiac patches.