Cardioprotective Effect of Pretreatment with A Single High-Dose Atorvastatin via Regulating Myocardial Uncoupling Protein 3 in a Rat Ischemia/Reperfusion Model

Objective: Since ischemia/reperfusion (I/R) can cause malignant arrhythmia, we explored the cardioprotective effect of pretreatment with a single and large dose of atorvastatin in the SD rat model. Methods: Rats were distributed into atorvastatin (Ator), I/R model and sham groups (n = 8/group) by random number table method. In Ator group, atorvastatin was gavaged with a single dose (80 mg/kg) 12 h before I/R. The heart was treated with ischemia for 30 min and then reperfusion for 2 h. Results: Myocardial infarct area was induced by I/R when compared with Sham group. Compared with I/R group, the pretreatment of atorvastatin significantly reduced area at risk/left ventricle (40.78 ± 1.39% vs. 46.76 ± 1.42%, p < 0.01), infarct area/area at risk (21.47 ± 1.65% vs. 29.16 ± 1.21%, p < 0.01), and lactate dehydrogenase activity (3056.17 ± 136.22 RFU vs. 3864.15 ± 162.92 RFU, p < 0.05). I/R induced uncoupling protein 3 (UCP3) in transcriptional and translational levels, but atorvastatin significantly increased the UCP3 expression when compared with I/R group, 1.91 ± 0.42 vs. 1.42 ± 0.21 fold (p < 0.05) in mRNA levels measured by RT-PCR and 2.07 ± 0.18 versus 1.45 ± 0.23 fold in protein levels by Western blots. Conclusion: A single high-dose atorvastatin pretreatment 12 h before I/R reduces the infarct area in I/R model in rats. The cardioprotection may be via regulating myocardial UCP3.

UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3 +/‐ ) to test the hypothesis that decreased UCP3 promotes left ventricular diastolic dysfunction during hypertension. Methods and Results Ucp3 +/‐ rats and ucp3 +/+ littermates fed a high‐salt diet (HS; 2% NaCl) and treated with angiotensin II (190 ng/kg per min for 28 days) experienced a similar rise in blood pressure (158±4 versus 155±7 mm Hg). However, UCP3 insufficiency worsened diastolic dysfunction according to echocardiographic assessment of left ventricular filling pressures (E/e’; 18.8±1.0 versus 14.9±0.6; P <0.05) and the isovolumic relaxation time (24.7±0.6 versus 21.3±0.5 ms; P <0.05), as well as invasive monitoring of the diastolic time constant (Tau; 15.5±0.8 versus 12.7±0.2 ms; P <0.05). Exercise tolerance on a treadmill also decreased for HS/angiotensin II‐treated ucp3 +/‐ rats. Histological and molecular analyses further revealed that UCP3 insufficiency accelerated left ventricular concentric remodeling, detrimental interstitial matrix remodeling, and fetal gene reprogramming during hypertension. Moreover, UCP3 insufficiency increased oxidative stress and led to greater impairment of protein kinase G signaling. Conclusions Our findings identified UCP3 insufficiency as a cause for increased incidence of left ventricular diastolic dysfunction during hypertension. The results add further support to the use of antioxidants targeting mitochondrial reactive oxygen species as an adjuvant therapy for preventing heart failure with preserved ejection fraction in individuals with obesity.

Cold Stress Activates the UCP3 Pathway via Gut Microbiota in Piglet

BackgroundThe gut microbiota plays a key role in the host metabolic thermogenesis by activating uncoupling protein 1 (UCP1) and increasing the browning process of white adipose tissue, especially in a cold environment. However, the crosstalk between gut microbiota and pigs, which lack functional UCP1 making them susceptible to cold, has rarely been illustrated. We used male piglets as a model to evaluate the host response to cold stress via the gut microbiota. ResultsWe found that host thermogenesis and insulin resistance with increased serum metabolites, such as glycocholic acid (GCA), glycochenodeoxycholate (GCDCA), and chenodeoxycholate (CDCA), and altered cecal microbiota compositions and functions under cold stress. Using transcriptomics technology, we found that cytochrome P450, family 8, subfamily b, polypeptide 1 (CYP8B1), FXR, FFAR2, and FFAR3, which are related to bile acid and short-chain fatty acid metabolism, increased in the liver under cold stress. In addition, the fat lipolysis genes CLPS, PNLIPRP1, carnitine palmitoyltransferase 1B (CPT1B), and uncoupling protein 3 (UCP3) were significantly increased in the fat of piglets under cold stress. However, microbiota depletion via treatment with mixed antibiotics weakened the effect on the genes CYP8B1, FFAR2, FFAR3, and CPT1B genes, indicating that the gut microbiota plays important roles in the host thermogenesis. ConclusionsOur results demonstrate that the gut microbiota-blood-liver and fat axis may regulate thermogenesis during cold acclimation in piglets.

Effect of -55C/T Polymorphism of Uncoupling Protein 3 Gene on Risk for New-Onset Diabetes in Chinese Peritoneal Dialysis Patients: A Prospective Cohort Study

<b><i>Background:</i></b> A high-glucose load in therapy can cause new-onset diabetes (NOD) in peritoneal dialysis (PD) patients. Genetic variability may result in risk modulation. <b><i>Objectives:</i></b> This study aims to investigate the association between −55C/T polymorphism of uncoupling protein 3 (UCP3) gene and the risk of NOD in PD patients. <b><i>Methods:</i></b> Nondiabetic incident PD patients between May 2005 and January 2017 were recruited (<i>n</i> = 154). −55C/T polymorphism of the UCP3 was genotyped in all participants at baseline. The cohort of wild group (−55CC) and mutant group (−55CT or −55TT) was built based on the genotypic difference. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) during the follow-up. Binary logistic regression was performed to explore the association between HOMA-IR and genotypes. Competitive risk analysis was used to analyze the impact of −55C/T polymorphism of UCP3 on risk for NOD. <b><i>Results:</i></b> The cohort was followed for up to 164.6 months (median: 58.3 months; interquartile range: 30.7 months). During the follow-up, 14 NODs occurred in the mutant group, while only 3 occurred in the wild group. Patients in the mutant group had higher HOMA-IR (Odd ratio: 2.210; 95% CI: 1.043–4.680; <i>p</i> = 0.038). Genotype with the variant T allele turned out to be an independent predictor for NOD morbidity (HR: 7.639; 95% CI: 1.798–32.451; <i>p</i> = 0.006). <b><i>Conclusions:</i></b> The variant of T allele of UCP3 −55C/T polymorphism was an independent predictor for NOD in PD patients. Early identification of the genotype may provide scientific basis for patients’ clinic management.