The Role of Rho-Associated Kinase in the Cognitive Benefits of the ACE Inhibitory Peptide LAP for Hypertension.

Introduction: This study assessed the effects of the synthesized ACE inhibitory peptide LAP (Leu-Arg-Pro-Val-Ala-Ala) on cognitive impairment in hypertensive rats.

Methods: Rho-associated coiled-coil containing protein kinase (ROCK) activity in peripheral blood mononuclear cells (PBMCs) was initially measured in elderly patients with hypertension and cognitive impairment using western blot analysis. The effect of LAP on the ROCK pathway was studied in a human cell line with ROCK1. Fifteenweek- old male spontaneously hypertensive rats (SHR) received intragastric LAP (500 μg/week) for eight weeks. Cognitive function was assessed using the Morris water maze test, and thoracic aorta remodeling was evaluated by determining the media/lumen ratio through immunohistochemistry. Amyloid beta (Aβ), phosphorylated tau (p-tau), and apoptotic neurons in the hippocampus were examined by western blot analysis and immunohistochemistry. Protein expression and activation related to the ROCK pathway, including moesin, myosin light chain (MLC), and myosin phosphatase target subunit (MYPT), were analyzed in the aorta and hippocampus using western blot and immunohistochemistry.

Results: Hypertensive patients with cognitive impairment showed increased phosphorylated/total myosin-binding subunit ratios in PBMCs, indicating higher ROCK pathway activity. In vitro, LAP reduced p-moesin levels, confirming ROCK inhibition. In vivo, oral LAP lowered blood pressure and heart rate in SHR models and improved cognitive function. LAP also reduced aortic remodeling, decreased hippocampal Aβ and p-tau deposition, reduced neuronal apoptosis, and increased neuronal survival. Mechanistically, LAP inhibited ROCK pathway activation in the aorta and hippocampus, similar to the ROCK inhibitor fasudil.

Discussion: Hypertension contributes to neurodegenerative changes through the activation of the ROCK signaling pathway. The study found that the ACE inhibitory peptide LAP not only sustainably lowered blood pressure, but also inhibited the ROCK pathway, reducing hippocampal Aβ and p-tau deposition, thereby offering a dual therapeutic approach for hypertension-related cognitive impairment.

Conclusion: LAP alleviated hypertension-related cognitive impairment in SHR by inhibiting the hippocampal ROCK pathway, showing therapeutic potential.