Renovascular Hypertension Induces Myocardial Mitochondrial Damage, Contributing to Cardiac Injury and Dysfunction in Pigs With Metabolic Syndrome.

BACKGROUND: Renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS) as well. Coexisting MetS and hypertension increases cardiovascular morbidity and mortality, but the mechanisms underlying cardiac injury remain unknown. We hypothesized that superimposition of MetS induces myocardial mitochondrial damage, leading to cardiac injury and dysfunction in swine RVH. METHODS: Pigs were studied after 16 weeks of diet-induced MetS with or without RVH (unilateral renal artery stenosis), and Lean controls (n = 6 each). Systolic and diastolic cardiac function were assessed by multidetector CT, and cardiac mitochondrial morphology (electron microscopy) and myocardial function in tissue and isolated mitochondria. RESULTS: Body weight was similarly higher in MetS groups vs. Lean. RVH groups achieved significant stenosis and developed hypertension. Mitochondrial matrix density and adenosine triphosphate production were lower and H2O2 production higher in RVH groups vs. Lean and MetS. Lean + RVH (but not MetS + RVH) activated mitophagy, which was associated with decreased myocardial expression of mitophagy-related microRNAs. MetS groups exhibited higher numbers of intermitochondrial junctions, which could have prevented membrane depolarization/activation of mitophagy in MetS + RVH. Cardiac fibrosis, hypertrophy (increased left ventricular muscle mass), and diastolic function (decreased E/A ratio) were greater in MetS + RVH vs. Lean + RVH. CONCLUSIONS: MetS+RVH induces myocardial mitochondrial damage and dysfunction. MetS + RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and therapeutic targets to ameliorate cardiac damage and dysfunction in patients with coexisting MetS and RVH.

Metabolic Syndrome Impairs 3D Mitochondrial Structure, Dynamics, and Function in Swine Mesenchymal Stem Cells.

Transplantation of autologous mesenchymal stem cells (MSCs) is an effective therapy for several diseases. Mitochondria modulate several important aspects of MSC function, but might be damaged by comorbidities and cardiovascular risk factors. We hypothesized that metabolic syndrome (MetS) compromises 3D mitochondrial structure, dynamics, and function in swine adipose tissue-derived MSCs. Domestic pigs were fed a Lean or MetS diet (n = 6 each) for 16 weeks. MSCs were collected from subcutaneous abdominal fat and their mitochondria analyzed using state-of-the-art Serial Block Face Electron Microscopy and 3D reconstruction. Mitochondrial dynamics (fusion/fission) were assessed by mRNA sequencing and Western blotting, and bioenergetics by membrane potential (TMRE), cytochrome-c oxidase (COX)-IV activity, and Seahorse Analyzer. Expression of mitochondria-associated microRNAs (mitomiRs) was measured by quantitative polymerase chain reaction (qPCR). MetS pigs developed obesity, hypertension, insulin resistance, and hyperlipidemia. Mitochondrial density was similar between the groups, but 3D mitochondrial and matrix volumes were lower in MetS-MSCs versus Lean-MSCs. Mitochondrial fission was higher, but fusion lower in MetS-MSCs versus Lean-MSCs, as were membrane potential, COX-IV activity, and ATP production. Contrarily, expression of the mitomiRs miR15a, miR-137, and miR-181c, which target mitochondrial genes that support mitochondrial structure, energy pathways, and dynamics, was higher in MetS-MSCs compared to Lean-MSCs, suggesting a potential to modulate their expression. MetS damages MSC 3D mitochondrial structure, dynamics, and function, and may modulate genes encoding for mitochondrial proteins. These observations support development of mitoprotective strategies to preserve the regenerative potency of MSCs and their suitability for autologous transplantation in patients with MetS.