Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis

• Published in: PloS one Vol. 16; no. 5; p. e0246600
• Main Authors: Ozcan, Lale, Kasikara, Canan, Yurdagul, Arif, Kuriakose, George, Hubbard, Brian, Serrano-Wu, Michael H., Tabas, Ira
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.05.2021; Public Library of Science (PLoS)
• Subjects: Allosteric properties; Allosteric Regulation - drug effects; Animal models; Animals; Aorta - pathology; Arteriosclerosis; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - enzymology; Atherosclerosis - pathology; Biology and Life Sciences; Biophysics; Blood glucose; Ca2+/calmodulin-dependent protein kinase II; Care and treatment; Cholesterol; Development and progression; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Drug dosages; Editing; Epidemics; Glucose; Glucose - metabolism; Health aspects; Health care facilities; Homeostasis - drug effects; Hyperglycemia; Insulin; Insulin resistance; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lipids - blood; Male; Mass spectra; Mass spectrometry; Medicine; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred C57BL; Necrosis; Obesity; Pathogenesis; Pharmacology, Experimental; Physiological aspects; Physiology; Plaque, Atherosclerotic - blood; Plaque, Atherosclerotic - enzymology; Plaque, Atherosclerotic - pathology; Plasma; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein kinases; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proteins; Public health; Quadrupoles; Reviews; Trifluoroacetic acid; United States; Louisiana; New York; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0246600

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr -/- mice. Ldlr -/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.