Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated.Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated.Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation.Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.

Exercise training has been reported to ameliorate heart dysfunction in both humans and animals after myocardial infarction (MI). Exercise-induced cardioprotective factors have been implicated in mediating cardiac repair under pathological conditions. These protective factors secreted by or enriched in the heart could exert cardioprotective functions in an autocrine or paracrine manner. Extracellular vesicles, especially exosomes, contain key molecules and play an essential role in cell-to-cell communication via delivery of various factors, which may be a novel target to study the mechanism of exercise-induced benefits, besides traditional signaling pathways. This review is designed to demonstrate the function and underlying protective mechanism of exercise-induced cardioprotective factors in MI, with an aim to offer more potential therapeutic targets for MI.

Myogenic mechanobiology governs how mechanical cues regulate myocyte organization, alignment, and functional maturation; however, in vitro platforms that enable quantitative control and real-time readout of myogenic mechanical microenvironments remain limited. Here, we engineered a pneumatic-driven organ-on-a-chip platform integrating six parallel culture units and a bead-embedded flexible PDMS membrane to deliver cyclic mechanical strain and enable quantitative stress–strain mapping in cardiomyocytes and skeletal muscle cells. Finite element-guided optimization ensured effective membrane deformation, and the platform generated stable and tunable cyclic strain with a strong linear relationship between applied negative pressure (50–700 mbar) and membrane stress and strain. Plasma treatment combined with type I collagen coating restored myogenic cell adhesion and growth on PDMS to levels comparable to standard culture conditions. Under 13% cyclic strain, both cardiomyocytes and skeletal muscle cells exhibited pronounced and highly uniform alignment, with cellular polarity oriented perpendicular to the stretch axis. Moreover, cyclic loading significantly enhanced the expression of contractile maturation markers, including MYH7 in cardiomyocytes and MYH6 in skeletal muscle cells (all p < 0.05), whereas expression of the differentiation regulator MyoG remained unchanged, indicating that mechanical stimulation preferentially promotes structural organization and contractile maturation rather than lineage commitment. Collectively, this quantitatively programmable organ-on-a-chip represents a bioengineered microdevice for studying myogenic mechanobiology, revealing conserved mechanosensitive alignment and maturation responses across myogenic lineages and providing a versatile framework for biomedical engineering research, disease modeling, and mechanotherapeutic screening.