RIMKLA promotes hypertension by activating PKM2 to trigger VSMC phenotype switch

Background: Hypertension affects around one billion adults worldwide, with abnormal glucose metabolism and vascular smooth muscle cell (VSMC) phenotype switch playing crucial roles in its pathogenesis. Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme, but its regulation and roles in VSMC phenotype switch and hypertension are unknown. Using the Gene Importance Calculator (GIC) to predict gene essentiality, we identified ribosomal modification protein rimK-like family member A (RIMKLA) as a highly relevant gene and explored its regulatory contributions to hypertension. Methods: Internal mammary arteries from patients with hypertension and normotension, as well as arteries from angiotensin II (Ang II)-induced hypertensive mice, salt-sensitive hypertensive Dahl/SS rats, and spontaneously hypertensive rats, were analyzed in this study. Adenoviruses and adeno-associated viruses were used for ex vivo and in vivo gene overexpression. VSMC-specific RIMKLA or PKM2 knockout mice were generated using the Cre-Loxp system. Arterial tension was measured by wire myography, and blood pressure was assessed by the tail-cuff method and remote radio-telemetry. Protein-protein interactions were determined by co-immunoprecipitation with mass spectrometry. Non-targeted metabolomics, in vitro phosphorylation, adenosine triphosphate (ATP), reactive oxygen species (ROS), and cytoplasmic calcium assays were performed to identify the signaling axis involved. Results: RIMKLA expression was increased in the medial layer of the internal mammary arteries of patients with hypertension, as well as in hypertensive rat and mouse arteries. RIMKLA overexpression in the mesenteric arteries of Sprague-Dawley rats significantly increased vessel contractility. VSMC-specific RIMKLA overexpression increased arterial contractility and blood pressure in mice. VSMC-specific RIMKLA deletion attenuated Ang II-induced hypertension in mice. Mechanistically, we identified RIMKLA as a scaffold protein that binds to protein-tyrosine phosphatase 1B (PTP1B) and PKM2. RIMKLA phosphorylated PTP1B at tyrosine (Tyr)66, leading to PKM2 dephosphorylation and activation at Tyr105. Once activated, PKM2 enhanced glucose metabolism, increased ROS production, and boosted ATP secretion, driving VSMC phenotype switch. RIMKLA-induced vasoconstriction and hypertension were reversed by VSMC-specific PKM2 deletion. Additionally, a PKM2 inhibitor reduced arterial contractility and blood pressure. Conclusions: RIMKLA functioned as a scaffold protein kinase, recruiting both PTP1B and PKM2, and orchestrating PTP1B phosphorylation and its subsequent recruitment to activate PKM2. These findings position RIMKLA as a key regulator of PKM2 activation, promoting VSMC phenotype switch and contributing to hypertension.