ArticleHypertension (Dallas, Tex. : 1979)2017
Proof of Principle for a Novel Class of Antihypertensives That Target the Oxidative Activation of PKG Iα (Protein Kinase G Iα).
Article in Hypertension (Dallas, Tex. : 1979), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 26 citations in OpenAlex.
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- Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Potential cardiotoxicity induced by Euodiae Fructus:Frontiers in pharmacology · 2022Article
- Discovery of the First Non-cGMP Mimetic Small Molecule Activators of cGMP-Dependent Protein Kinase 1 α (PKG1α).ACS medicinal chemistry letters · 2021Article
- Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension.Advances in experimental medicine and biology · 2021Review
- Disruption of Pressure-Induced CaHypertension (Dallas, Tex. : 1979) · 2020Article
- Blood Pressure-Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of cGMP-Dependent Protein Kinase.Circulation · 2019Article
- Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension.JCI insight · 2019Article
- Meeting report of the 8Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
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4 authors at 2 institutions in 1 country.
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Abstract
Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in PKG Iα (protein kinase G Iα) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. Consequently, we developed an assay and screened for electrophilic drugs that activate PKG Iα by selectively targeting C42, as such compounds have potential as novel antihypertensives with a mechanism of action that differs from current therapies. In this way, a drug that we termed G1 was identified, which targets C42 of PKG Iα to induce vasodilation of isolated resistance blood vessels and blood pressure lowering in a mouse model of angiotensin II-induced hypertension. In contrast, these antihypertensive effects were deficient in angiotensin II-induced hypertensive C42S PKG Iα knockin mice. These transgenic mice were engineered to have the reactive cysteinyl thiol replaced with a hydroxyl so that it cannot react with endogenous vasodilatory oxidants or electrophiles such as drug G1. These studies, therefore, provide validation of PKG Iα C42 as the target of G1, as well as proof-of-principle for a new class of antihypertensive drugs that have potential for further development for clinical use in humans.
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