Endoplasmic Reticulum Stress: A Novel Target for the Prevention and Treatment of Hypertension and Its Related Diseases

Endoplasmic reticulum stress (ERS) emerges as a critical pathophysiological nexus in hypertension and related cardiovascular diseases. Chronic ERS activation via the IRE1α-XBP1, ATF6, and PERK pathways drives vascular endothelial dysfunction (reduced NO bioavailability, increased ET-1), renin-angiotensin system (RAS) hyperactivation, sympathetic overactivation, and vascular smooth muscle cell (VSMC) maladaptive proliferation/apoptosis, collectively promoting hypertension progression and end-organ damage. Pharmacological targeting of ERS demonstrates therapeutic promise: chemical chaperones 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) stabilise proteostasis, reduce oxidative stress, and inhibit apoptosis; antioxidants N-acetylcysteine (NAC) and melatonin attenuate ERS-oxidative stress crosstalk. Notably, conventional antihypertensives-ACE inhibitors and angiotensin receptor blockers (ARBs)-exert ancillary benefits by suppressing ERS beyond their primary RAS blockade. Preclinical evidence supports the efficacy of these strategies in reversing hypertensive pathophysiology. Future research must prioritise isoform-selective ERS modulator development, validation in human trials, biomarker discovery, and elucidating ERS roles in therapy-induced hypertension. Targeting ERS represents a transformative mechanotherapeutic paradigm for precision hypertension management.