Activating PKA signaling increases exosome production and attenuates cerebral ischemia-reperfusion injury by regulating Cx43 expression

• Published in: Journal of stroke and cerebrovascular diseases 2024-12, Vol.33 (12), p.108000, Article 108000
• Main Authors: Chen, Wei, Qin, Yaxin, Wang, Zhigang, Chen, Pandi, Zhu, Guangyao, Li, Shiwei, Wang, Hongcai, Liu, Xuelan, Chen, Maosong, Li, Zengpan, Ye, Gengfan
• Format: Article
• Language: English
• Subjects: Animals; Astrocyte; Astrocytes - metabolism; Astrocytes - pathology; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain - metabolism; Brain - pathology; Brain Edema - metabolism; Brain Edema - pathology; Brain Edema - prevention & control; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Cells, Cultured; Cognition; Connexin 43; Connexin 43 - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; Enzyme Activation; Exosome; Exosomes - metabolism; Ischemia-reperfusion injury; Male; Memory; Morris Water Maze Test; PKA; Protein Kinase Inhibitors - pharmacology; Rats, Inbred Lew; Recovery of Function; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Signal Transduction; Tetraspanin 28 - metabolism; Tetraspanin 30 - metabolism
• ISSN: 1052-3057; 1532-8511; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2024.108000

Connexin 43 (Cx43) plays a crucial role in mediating intracellular communication and facitating the interaction between exosomes and recipient cells. This study investigates whether the activation of cAMP/protein kinase A (PKA) can regulate exosomal Cx43 expression and contribute to the functional recovery following ischemia-reperfusion (I/R) injury. An intraluminal vascular occlusion was performed on Lewis rats to simulate I/R injury. Concurrently, a PKA activator (8-Bromo-cAMP, 5 mg kg-1) or PKA inhibitor (H 89 2HCl, 20 mg kg-1) was administered intravenously via the tail vein (n = 10). Exosomes were isolated from cerebrospinal fluid, and the expression of exosomal markers (CD63 and CD81) and Cx43 was analyzed using Western blot. The expression of CD63 and CD81 in astrocytes was measured to assess exosome uptake. Spatial learning and memory capability were evaluated using the Morris water maze test. 8-Bromo-cAMP significantly increased exosome release in cerebrospinal fluid, accompanied by elevated Cx43 expression. Additionally, 8-Bromo-cAMP enhanced exosome uptake by astrocytes, alleviated blood-brain barrier damage and edema, and improved cognitive function. PKA activation enhances exosome production, promotes cognitive function recovery, and attenuates cerebral I/R injury by up-regulating exosomal Cx43 expression.