The key findings of the present study were: (i) PYR, a cholinesterase inhibitor, protects against cardiac remodeling induced by pressure overload via inhibition of RAS activation; (ii) ACh suppresses Ang II-induced cell proliferation, migration, and transformation as well as collagen synthesis, partially through the TGF-β1/Smad3 signaling pathway; (iii) M2 AChR plays a pivotal role in ACh anti-fibrotic action in CFs. The gene discussed is SMAD3; the disease is myalgic encephalomeyelitis/chronic fatigue syndrome.