Photobiomodulation therapy inhibits ISO-induced myocardial remodeling in mice through modulating TGF-β/Smad7 and...

This study elucidates the mechanism by which Photobiomodulation (PBM) suppresses the progression of isoproterenol (ISO) -induced heart failure (HF) in mice and investigates the effects of PBM therapy on ventricular remodeling in vivo. Our results showed that PBM therapy effectively alleviated ISO-induced cardiac dysfunction and myocardial fibrosis as well as inhibiting cardiomyocytes disorganization and apoptosis. Meanwhile, PBM also attenuated activation of fibroblasts and accumulation of myofibroblasts, inhibited Endothelial-Mesenchymal Transition (EndMT) and Transforming Growth Factor-β (TGF-β) associated inflammation. Finally, we revealed that PBM exerted its cardioprotective effects through coordinated modulation of TGF-β/Smad7 and PI3K/AKT pathways.This dual modulation culminates in attenuated myocardial remodelling and improved cardiac function.

The characteristics of adverse ventricular remodeling include chamber dilation, wall thickening and diminished contractility which are the typical histopathological changes of HF. PBM effects via radiative, resonant and thermal mechanisms. While PBM therapy demonstrates efficacy in chronic disease management, the precise molecular mechanisms underlying its cardioprotective effects, particularly in preventing or reversing cardiac remodeling, remain incompletely defined. This study aimed to evaluate the therapeutic efficacy of PBM against HF and delineate the precise molecular mechanisms involved in its modulation of ventricular remodeling.

Forty-eight adult male C57BL/6 mice were randomly allocated to four groups: control mice (CON), ISO-induced mice (ISO), PBM-treated mice (ISO+PBM) and PBM-only mice (PBM). ISO and ISO+PBM groups were injected intraperitoneally with ISO 10mg/(kg·d) daily for 4 weeks. The PBM and ISO+PBM mice were treated with Photobiomodulation for 4 weeks. 4-week later, Cardiac function was evaluated by cardiac ultrasound. HE staining was performed to assess myocardial histopathological changes. Masson staining, TUNEL fluorescence, immunofluorescence, immunohistochemistry, and western blotting were employed to quantify fibrosis and apoptosis in myocardial tissues. Bioinformatics analysis and Western blotting were conducted to identify the potential underlying mechanisms of PBM in protecting ISO-induced myocardial injury.

PBM therapy significantly mitigated ISO-induced HF in C57BL/6 mice. PBM therapy suppressed inflammatory mediator accumulation, cardiomyocyte apoptosis, and cardiac fibrosis. During cardiac fibrosis, PBM blunted fibroblast expansion by suppressing EndMT and, via up-regulation of Smad7 in fibroblasts and myofibroblasts, antagonised TGF-β signaling and the associated inflammatory response. Bioinformatics analysis identified the PI3K/AKT pathway as indispensable for β-adrenergic receptor-mediated cardiac dysfunction. PBM restores PI3K/AKT/CREB signaling homeostasis, thereby conferring therapeutic benefit in HF.

Our findings demonstrate that PBM therapy effectively targets two pivotal pathways to mitigate ISO-induced ventricular remodeling: (1) upregulating Smad7 to constrain TGF-β-driven cardiac fibrosis, and (2) suppressing PI3K/AKT/CREB phosphorylation to mitigate maladaptive remodeling. This dual-pathway regulatory mechanism is the basis for PBM's efficacy in alleviating HF. Therefore, PBM represents a mechanistically based and promising non-pharmacological strategy against pathological cardiac remodeling.