Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1.

Decreased serum adiponectin levels in type 2 diabetes has been linked to the onset of mitochondrial dysfunction in diabetic complications by impairing AMPK-SIRT1-PGC-1α signaling via impaired adiponectin receptor 1 (AdipoR1) signaling. Here, we aimed to characterize the previously undefined role of disrupted AdipoR1 signaling on the mitochondrial protein composition of cardiac, renal, and hepatic tissues as three organs principally associated with diabetic complications. Comparative proteomics were performed in mitochondria isolated from the heart, kidneys and liver of Adipor1 -/- mice. A total of 790, 1,573, and 1,833 proteins were identified in cardiac, renal and hepatic mitochondria, respectively. While 121, 98, and 78 proteins were differentially regulated in cardiac, renal, and hepatic tissue of Adipor1-/- mice, respectively; only 15 proteins were regulated in the same direction across all investigated tissues. Enrichment analysis of differentially expressed proteins revealed disproportionate representation of proteins involved in oxidative phosphorylation conserved across tissue types. Curated pathway analysis identified HNF4, NRF1, LONP, RICTOR, SURF1, insulin receptor, and PGC-1α as candidate upstream regulators. In high fat-fed non-transgenic mice with obesity and insulin resistance, AdipoR1 gene expression was markedly reduced in heart (-70%), kidney (-80%), and liver (-90%) (all P < 0.05) as compared to low fat-fed mice. NRF1 was the only upstream regulator downregulated both in Adipor1-/- mice and in high fat-fed mice, suggesting common mechanisms of regulation. Thus, AdipoR1 signaling regulates mitochondrial protein composition across all investigated tissues in a functionally conserved, yet molecularly distinct, manner. The biological significance and potential implications of impaired AdipoR1 signaling are discussed.

Myocardial mitochondrial dysfunction in mice lacking adiponectin receptor 1.

Hypoadiponectinemia is an independent predictor of cardiovascular disease, impairs mitochondrial function in skeletal muscle, and has been linked to the pathogenesis of Type 2 diabetes. In models of Type 2 diabetes, myocardial mitochondrial function is impaired, which is improved by increasing serum adiponectin levels. We aimed to define the roles of adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) in adiponectin-evoked regulation of mitochondrial function in the heart. In isolated working hearts in mice lacking AdipoR1, myocardial oxygen consumption was increased without a concomitant increase in cardiac work, resulting in reduced cardiac efficiency. Activities of mitochondrial oxidative phosphorylation (OXPHOS) complexes were reduced, accompanied by reduced OXPHOS protein levels, phosphorylation of AMP-activated protein kinase, sirtuin 1 activity, and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling. Decreased ATP/O ratios suggested myocardial mitochondrial uncoupling in AdipoR1-deficient mice, which was normalized by lowering increased mitochondrial 4-hydroxynonenal levels following treatment with the mitochondria-targeted antioxidant Mn (III) tetrakis (4-benzoic acid) porphyrin. Lack of AdipoR2 did not impair mitochondrial function and coupling in the heart. Thus, lack of AdipoR1 impairs myocardial mitochondrial function and coupling, suggesting that impaired AdipoR1 signaling may contribute to mitochondrial dysfunction and mitochondrial uncoupling in Type 2 diabetic hearts.

Impact of chronic kidney disease on long-term clinical outcomes after percutaneous coronary intervention with drug-eluting or bare-metal stents.

Chronic kidney disease (CKD) is associated with adverse outcomes after coronary bare-metal stent (BMS) and drug-eluting stent (DES) implantation, but it is unclear which stent type is associated with lower risk for morbidity and mortality in this population. Uniform treatment standards during coronary stent implantation and a median follow-up period of 2.8 years characterize the FReIburg STent (FRIST) registry, designed as a long-term outcome evaluation of a single tertiary referral cardiovascular center. CKD, defined as creatinine clearance <60 mL/min, was present at baseline in 180 (12%) of 1502 consecutive patients undergoing coronary stent intervention. Patients received first-generation DES (n = 117) or BMS (n = 63). Kaplan-Meier and multivariate Cox model analyses were applied to compare survival rates and adjust for existing clinical, procedural, and angiographic differences between the patients. The primary end point was mortality (cardiac and noncardiac death) and secondary end points were recurrent myocardial infarction, stent thrombosis, target vessel revascularization, sepsis, and major bleeding. Patients with a glomerular filtration rate <60 mL/min had a higher mortality rate (28.3% vs. 10.1%, P < 0.001) than patients with a good renal function. In patients with CKD, there was no difference in mortality rates in the BMS vs. the DES group (hazard ratio, 0.971; 95% confidence interval, 0.48-1.954). In summary, patients with CKD have significantly higher rates of death, but there appears to be no difference in long-term clinical outcomes of first-generation DES compared with BMS implantation during primary percutaneous coronary intervention.