DAPK1 acts as a positive regulator of hypertension via induction of vasoconstriction.

Abstract

Death-associated protein kinase 1 (DAPK1) is a tumor suppressor gene involved in apoptosis, autophagy, and tumor progression. However, its role in hypertension (HTN) remains largely unexplored and lacks systematic evaluation. We administered adeno-associated virus (AAV) harboring short hairpin RNA targeting DAPK1 or control short hairpin RNA to male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats. Additionally, wildtype and DAPK1 knockout mice were infused with angiotensin II (Ang II) or saline for four weeks. Male C57BL/6 mice underwent a four-week Ang II infusion and were treated with TC-DAPK6, a selective DAPK1 inhibitor. We examined the abdominal aortas (AAs) of mice and rats for pathological changes, measured blood pressure (BP) and pulse wave velocity using noninvasive BP methods, ultrasound, and hematoxylin and eosin staining. The role of DAPK1 in early HTN was further assessed through immunofluorescence, ex vivo isometric constriction of the AA, RNA sequencing, Western blot, and immunohistochemistry. Our study demonstrated that the targeted inhibition of DAPK1 with AAV significantly ameliorated HTN in SHRs and reduced damage to the AAs and target organs, including the heart and kidneys. Meanwhile, DAPK1 knockout or inhibition in mice significantly ameliorates Ang II-induced HTN in mice, as well as reducing damage to the AAs and target organs, including the heart and kidneys. Mechanistically, DAPK1 inhibition prevents myosin light chain (MLC) phosphorylation at serine 19, reducing vasoconstriction and protecting against HTN. In conclusion, DAPK1 is involved in HTN pathogenesis by regulating the MLC pathway to mediate vascular constriction, highlighting potential as a therapeutic target for HTN.