16 rhesus monkeys were assigned an atherogenic diet (high fat and high cholesterol diet: HCD) and 10 monkeys a control diet (standard diet: SD) after baseline measurements were collected; blood pressure, pulse wave velocity (PWV) and lipid profile. At baseline, cholesterol showed no differences between the control and treated groups. However, at the second follow-up after 6 months, cholesterol levels in the HCD group increased 2-fold compared to controls (p<0.0001) and remained stable until the end of experiment (2-year study). Arterial tissue was collected at the time of sacrifice. Histochemical observation and morphological analysis indicated that age increases intimal thickness along with atherosclerotic burden in monkeys fed normal diets. Importantly, HCD dramatically increases fat deposition within arterial walls in the old monkeys. We also found that an HCD increases adverse histopathologic events and plaque burden and vulnerability, which are closely associated with changes in intimal thickening, fat deposition, and inflammation. Furthermore, we found that the HCD reprograms the aged arterial wall via the damage of endothelial integrity and an increase of macrophage infiltration, foam cell formation, and fat deposits, leading to a vulnerable thickened intima for the accelerated progression of adverse vascular wall events, including atherosclerotic burden and plaque vulnerability. It is known that central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of atherosclerosis burden and vulnerability in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic PWV, is a major risk factor for adverse clinical events. In rhesus monkeys, a 2-year diet, high in fat and sucrose (HFS), increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening, increases PWV and arterial inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall are driven by genomic and proteomic signatures of oxidative stress and inflammation. Very importantly, resveratrol, a SIRT2 agonist, treatment prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV and arterial inflammation. Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates stiffening, calcification, and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is a clinically relevant goal. Recent studies demonstrated that augmented collagen deposition and adverse matrix remodeling strongly correlate with an increased expression of the collagen-specific receptor tyrosine kinase, Discoidin Domain Receptor 2 (DDR2), in the aorta of rhesus monkeys fed a HFS diet for 24 months. Together with data demonstrating DDR2-dependence of collagen gene expression in vascular cells exposed to hyperglycemic conditions in vitro, our findings provide robust evidence that DDR2 is an unrecognized determinant of vascular fibrosis associated with vascular pathologies such as calcification and atherosclerosis, and hence a therapeutic molecular target. Again, we also show that resveratrol attenuates collagen deposition and remodeling in the vascular wall via the inhibition of DDR2 expression, which is associated with decreases in elastin degradation and calcification and atherosclerosis in nonhuman primates. In collaboration with Dr. Engler (Department of Bioengineering, University of California, San Diego), we found when studying the cardiac proteomes of both young and old rhesus monkeys and rats, certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression markedly increased median life span in flies. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity in flies, rats, and monkeys. In collaboration with Dr. Wang Wang (University of Washington, Seattle), we investigate the regulation and roles of a mitochondrial fission protein, the dynamin-related protein 1 (Drp1), in lipid overload-induced cardiomyocyte death and heart dysfunction in nonhuman primates. High fat and high cholesterol diet (HCD, 2 years) in monkeys also caused myocardial damage and activated Drp1 in the heart. Interestingly, HCD decreased NAD+ level and increased Drp1 acetylation. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation and protein level, which were abolished by restoring the decreased NAD+ level. Drp1 acetylation at lysine 642 (K642) was increased by HCD in cardiomyocytes. The non-acetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. These findings uncover a novel mechanism contributing to lipid overload-induced adverse myocardial remodeling and dysfunction. Excessive lipid supply created an intracellular environment to facilitate Drp1 acetylation, which increased its activity and mitochondrial translocation causing cardiomyocyte dysfunction and cell death. Thus, Drp1 could be a critical mediator for lipid overload-induced adverse myocardial remodeling as well as a potential target for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000238-12
Application #
10007325
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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