AdipoRon

The internal thoracic artery (ITA) is the first choice for coronary artery bypass grafting. However, the effect of perivascular adipose tissue (PVAT) on its vasomotor regulation has not been fully studied. PVAT may secrete adipokines, such as adiponectin, which plays a role in vasodilation, thus potentially enhancing graft function and antispasmodic ability.

Human ITA rings were obtained from patients undergoing coronary artery bypass grafting and mounted in a wire myograph. Rings were precontracted with U46619 (10^-7 M), followed by cumulative application of synthetic agonist of adiponectin receptors (AdipoRon) (10^-8 to 10^-4 M) or calcium ionophore (A23187) (10^-9 to 10^-4 M). Groups included endothelium-intact or denuded rings, with or without PVAT, and with or without the nitric oxide synthase inhibitor Nω-nitro-L-arginine. PVAT samples were also incubated with AdipoRon or A23187 for 24 hours, and adiponectin secretion was measured by enzyme-linked immunosorbent assay.

Both AdipoRon and A23187 induced concentration-dependent vasorelaxation. PVAT significantly enhanced vasorelaxation compared with PVAT-removed rings (P < .001). Under nitric oxide synthase inhibition, PVAT presence still augmented relaxation (P < .001), and in PVAT presence rings lacking both endothelium and nitric oxide, partial A23187-induced relaxation was preserved (P < .001). Enzyme-linked immunosorbent assay showed that AdipoRon had no significant effect (P = .14), whereas A23187 significantly increased adiponectin secretion (P < .001), indicating a calcium-dependent mechanism of adiponectin release.

PVAT exerts potent vasodilatory effects on human ITA, even in the absence of nitric oxide and endothelium. These findings support the physiological benefit of preserving PVAT, as in pedicled ITA grafts, which may enhance graft relaxation and reduce or ameliorate vasospasm during coronary artery bypass grafting.

Ischemic stroke is a leading cause of death and disability with limited therapeutic options. Neuroinflammation, particularly microglial activation and phenotypic modulation, plays a crucial role in ischemic cerebral injury. AdipoRon (APR), an adiponectin receptor agonist, shows neuroprotective effects, but its role in modulating microglial phenotypic states after ischemic stroke remains unclear. Using a transient middle cerebral artery occlusion (tMCAO) model, we demonstrated that APR treatment significantly ameliorated neurological deficits caused by ischemic injury. Our findings revealed that APR markedly reduced CD16 expression while enhancing CD206 expression in microglia, suggesting its neuroprotective actions are closely associated with microglial phenotypic modulation. We further explored APR effects on autophagy, given its crucial role in regulating microglial phenotypic states. APR significantly enhanced autophagy, and this enhancement was partially reversed by 3-methyladenine (3-MA), concomitantly reversing APR-induced CD206-associated microglial phenotype and its anti-inflammatory effects. To delineate the underlying mechanism, we examined adiponectin receptor signaling and downstream AMPK pathway involvement. Using siRNA-mediated knockdown of AdipoR1 and AMPK inhibitor Compound C, we observed marked reduction in autophagy levels and impairment of APR regulatory effects on microglial phenotypic modulation and inflammation. Collectively, our findings indicate that AdipoRon alleviates ischemic cerebral injury by activating the AdipoR1-AMPK signaling pathway, which subsequently enhances autophagy to promote a microglial phenotypic shift characterized by decreased CD16 and increased CD206 expression. These findings provide novel insights into APR neuroprotective mechanisms and highlight its potential as a therapeutic agent for ischemic stroke.