Gary Owens, PhD, the Robert M. Berne Professor of Cardiovascular Research, Molecular Physiology and Biological Physics and director of the School of Medicine’s Robert M. Berne Cardiovascular Research Center, was awarded a $3.2 million NIH R01 grant for a project titled “Role of Smooth Muscle Cell Insulin Resistance and Systemic Metabolic Dysfunction in Atherosclerosis Development and Late-Stage Lesion Pathogenesis.”
Rupture or erosion of advanced atherosclerotic lesions are the underlying cause of most heart attacks (myocardial infarction or MI) and stroke which together are the leading causes of death in the USA and globally. Despite statin treatment and lifestyle changes to reduce LDL cholesterol the incidence of MI and strokes are on the rise due largely to the global epidemic of obesity, metabolic syndrome (MetS), and early onset T2D characterized by development of insulin resistance in the cells in your body, impaired glucose uptake, and high blood glucose or hyperglycemia. Indeed, more than half of the mortality in T2D is caused by cardiovascular complications. Human histopathological studies have shown that lesions prone to plaque rupture have a thin fibrous cap and a high ratio of macrophages relative to smooth muscle cells (SMC). These plaque-destabilizing characteristics occur at a higher prevalence in atherosclerotic lesions of diabetics and in women versus men. However, the mechanisms by which insulin resistance, hyperglycemia, and other metabolic abnormalities in T2D-MetS exacerbate atherosclerotic disease development and progression are poorly understood.
The Owens Lab previously demonstrated (Newman et al. 2022 Nature Metabolism) that although multiple cell types contribute to formation of the fibrous cap, long-term plaque stability is dependent on SMC transitioning from its normal contractile state to an extracellular matrix producing myofibroblast (MF)-like state critical for formation and maintenance of a thick, mechanically stable, protective fibrous cap. Moreover, they provided evidence that this SMC to MF transition was dependent on the cells switching their energy production from oxidative (aerobic) metabolism to aerobic glycolysis, a much less efficient pathway that is dysregulated in T2D and dependent on high glucose uptake. Studies in this grant are testing the hypothesis that development of insulin resistance in SMC combined with metabolic abnormalities associated with T2D-MetD impair the ability of SMC to form the protective fibrous cap resulting in increased probability of plaque rupture triggering an MI or stroke.
Consistent with their hypothesis, they found that experimental induction of insulin resistance in SMC by knocking out one allele of two genes required for insulin signaling (IRS1 and IRS2) in Ldlr-deficient atherosclerosis prone mice fed a WD for 18 weeks led to a reduction in SMC-derived MF-like cells in the fibrous cap of atherosclerotic lesions. Moreover, of major interest, they found that this change was only observed in female but not male mice. These results provide exciting, albeit preliminary evidence, that female mice may have a reduced capacity to adapt to impaired insulin signaling in SMC as compared to male mice and that this results in reduced SMC investment into the fibrous cap and reduced plaque stability. Additional studies are in progress to determine potential mechanisms by which impaired insulin-IGF1 signaling in SMC contributes to late-stage lesion pathogenesis in humans with T2D/MetS and if these impact women more than men. They are also determining if global insulin resistance and the associated metabolic changes, including hyperglycemia, promote atherosclerosis development and late-stage lesion pathogenesis by inducing detrimental changes in SMC function using novel mouse genetic models of pre-T2D, T2D, and T2D-Mets generated by a Senior Research Scientist in the Owens Laura Shankman (PhD) in collaboration with Susanna Keller (MD).
The ultimate goal of studies is to identify novel therapeutic interventions for promoting increased plaque stability in patients with T2D-MetS and customizing these therapies to the individual patient based on genetic and metabolic profiling. Studies are being done in collaboration with Mete Civelek, PhD at UVA, as well as Gerard Pasterkamp, MD, and Hester den Ruijter, PhD, from the University Medical Center Utrecht in The Netherlands and Morris White, MD, from Harvard University.
Learn more about Dr. Owens’ research.