Voluntary exercise increases cholesterol efflux but not macrophage reverse cholesterol transport in vivo in mice

Physical exercise beneficially impacts on the plasma lipoprotein profile as well as on the incidence of cardiovascular events and is therefore recommended in primary and secondary prevention strategies against atherosclerotic cardiovascular disease. However, the underlying mechanisms of the protective effect of exercise remain largely unknown. Therefore, the present study tested the hypothesis that voluntary exercise in mice impacts on cholesterol efflux and in vivo reverse cholesterol transport (RCT). After two weeks of voluntary wheel running (average 10.1 ± 1.4 km/day) plasma triglycerides were lower (p < 0.05), while otherwise lipid and lipoprotein levels did not change. Macrophage cholesterol efflux towards plasma was significantly increased in running (n = 8) compared to sedentary (n = 6) mice (14.93 ± 1.40 vs. 12.33 ± 2.60%, p < 0.05). In addition, fecal excretion of bile acids (3.86 ± 0.50 vs. 2.90 ± 0.51 nmol/d, p = 0.001) and neutral sterols (2.75 ± 0.43 vs. 1.94 ± 0.22 nmol/d, p < 0.01) was significantly higher in running mice. However, RCT from macrophages to feces remained essentially unchanged in running mice compared with sedentary controls (bile acids: 3.2 ± 1.0 vs. 2.9 ± 1.1 % of injected dose, n.s.; neutral sterols: 1.4 ± 0.7 vs. 1.1 ± 0.5 % injected dose, n.s.). Judged by the plasma lathosterol to cholesterol ratio, endogenous cholesterol synthesis was increased in exercising mice (0.15 ± 0.03 vs. 0.11 ± 0.02, p < 0.05), while the hepatic mRNA expression of key transporters for biliary cholesterol (Abcg5/g8, Sr-bI) as well as bile acid (Abcb11) and phospholipd (Abcb4) excretion did not change. These data indicate that the beneficial effects of exercise on cardiovascular health include increased cholesterol efflux, but do not extend to other components of RCT. The increased fecal cholesterol excretion observed in running mice is likely explained by higher endogenous cholesterol synthesis, however, it does not reflect increased RCT in the face of unchanged expression of key transporters for biliary sterol secretion

Evaluating Emotional Well-Being after a Short-Term Traditional Yoga Practice Approach in Yoga Practitioners with an Existing Western-Type Yoga Practice

The purpose of the present study was to examine the influence of a traditional yoga practice approach (morning daily practice, TY) compared to that of a Western yoga practice approach (once-twice weekly, evening practice, WY) on determinants of emotional well-being. To that end, in a pre/posttest between-subject design, measures of positive (PA) and negative affect (NA), mindfulness, perceived stress, and arousal states were taken in 24 healthy participants (20 women; mean age: 30.5, SD = 8.1 years) with an already existing WY practice, who either maintained WY or underwent a 2-week, five-times-per-week morning practice (TY). While WY participants maintained baseline values for all measures taken, TY participants showed significant beneficial changes for PA, NA, and mindfulness and a trend for improved ability to cope with stress at the completion of the intervention. Furthermore, TY participants displayed decreased subjective energy and energetic arousal. Altogether, findings indicate that the 2-week TY is beneficial over WY for improving perceived emotional well-being. The present findings (1) undermine and inspire a careful consideration and utilization of yoga practice approach to elicit the best benefits for emotional well-being and (2) support yoga as an evidence-based practice among healthy yoga practitioners

Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

<p>Abstract</p> <p>Background</p> <p>Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI.</p> <p>Methods</p> <p>Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed.</p> <p>Results</p> <p>Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model.</p> <p>Conclusion</p> <p>Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.</p

Interaction of exercise and simvastatin on myocardial ischemia-reperfusion (I/R) injury and post-ischemic cardiac function

Simvastatin is one of the statins, which are a class of drugs originally developed to fight cardiovascular disease by lowering cholesterol. However, it is now clear that they have effects independent of cholesterol. For example, statin therapy, like exercise, induces adaptations within the heart that protect it against I/R injury. Patients are frequently advised to undergo a combination treatment of statins and chronic exercise, although little is known about how this combination treatment affects cardioprotective adaptations. Both treatments appear to exert their cardioprotective effects through different mechanisms, therefore it appears plausible that combining the two treatments would provide added cardioprotection than either treatment alone. Purpose: To investigate the effects of a combination treatment of statins and exercise upon parameters of post-ischemic myocardial function and damage. Methods: Female Sprague-Dawley rats (6 months of age) were separated into 4 groups for a period of 4 weeks: Sedentary (S, n=10), sedentary plus 10 mg simvastatin (Zocor®)/kg body wt/ day (SD, n=9), exercise (R, n=9), and exercise plus simvastatin (RD, n=9). R and RD were exercised identically on a treadmill for 5 days/week at an intensity of about 70% VO2max and for a duration that was gradually increased to 60 min/day. Twenty-four hrs following the last exercise bout, isolated perfused working hearts were subjected to 30 min of global ischemia followed by 30 min of normoxic reperfusion. Coronary effluents were used to determine lactate dehydrogenase (LDH) leakage and prostaglandin generation. Results: Cardiac function was similar in all groups prior to ischemia. Post I/R recovery of cardiac function in S was 17.6 [greater than or equal to]6.6% of pre-ischemic cardiac output times systolic pressure. Recovery was significantly higher in SD (37.7[greater than or equal to]7.7%) and R (40.1[greater than or equal to]7.8%) and tended to be highest in RD (49.7[greater than or equal to]7.1%). SD had significantly higher pre-ischemic coronary flow per g heart weight (CF/g) than all other groups. At 10 min post-ischemia, simvastatin treatment significantly increased CF/g compared to S (p<0.05). Exercise had an effect on increasing post-ischemic myocardial efficiency and RD had significantly higher post-ischemic myocardial efficiency vs. S (p<0.05). Compared to S, LDH leakage during reperfusion was dramatically decreased in SD, R and RD by approximately similar amounts. Simvastatin treatment doubled the basal production of protective prostaglandins, whereas exercise did not significantly alter their production and combining both treatments yielded a lower prostaglandin release than simvastatin treatment. SD had s significantly higher basal prostaglandin release than R (p<0.05). Conclusion: Although the combination treatment of simvastatin and exercise did not result in a statistically significant addition in cardioprotection compared to either treatment alone, there was a trend for improved parameters of post-ischemic cardiac function and damage upon combining both treatments compared to each treatment alone. Specifically, the prostaglandin, CF/g and efficiency data suggest that exercise and statininduced cardioprotection against I/R injury appears to occur by different mechanisms and combining the two treatments may provide greater protection than either alone.Kinesiology and Health Educatio

Interventions in the metabolic syndrome: bile acid sequestration and exercise

The prevalence of the metabolic syndrome (MetS) has reached alarming dimensions in the Western World. MetS is comprised of a multitude of risk factors and can lead to serious complications like type 2 diabetes and atherosclerosis. Bile acid sequestrants (BAS), pharmacological agents that increase the fecal excretion of bile acids, and physical activity improve MetS and act beneficial in decreasing high blood glucose and high cholesterol levels, two components of MetS. However, underlying mechanisms are elusive. We evaluated whether the BAS and physical activity induced improvements in MetS are underlying specific changes in glucose-and cholesterol-handling in specific mouse models paralleling human disease. We found that BAS decrease blood glucose levels by peripheral actions and not by modulations of liver glucose handling. Specifically, we found BAS to increase the clearance of blood glucose which coincided with a number of parameters indicating improved peripheral insulin sensitivity and utilization. Additionally, we found BAS treatment to substantially reduce atherosclerosis development in atherosclerosis-prone mice which is most likely mediated by a switch from bodily cholesterol accumulation to cholesterol loss. We further established that physical activity beneficially modulates cholesterol metabolism by enhancing its fecal excretion especially as bile acids but also as neutral sterols. This coincided with a reduced development of atherosclerosis and hepatic fat storage. Intriguingly, we found a negative correlation between the amount of physical activity and atherosclerosis development. Altogether, the studies of this thesis provide novel insights on how BAS and physical activity beneficially affect MetS risk factors and its complications.

Exercise Enhances Whole-Body Cholesterol Turnover in Mice

MEISSNER, M., R. HAVINGA, R. BOVERHOF, I. KEMA, A. K. GROEN, and F. KUIPERS. Exercise Enhances Whole-Body Cholesterol Turnover in Mice. Med. Sci. Sports Exerc., Vol. 42, No. 8, pp. 1460-1468, 2010. Purpose: Regular exercise reduces cardiovascular risk in humans by reducing cholesterol levels, but the underlying mechanisms have not been fully explored. Exercise might provoke changes in cholesterol and bile acid metabolism and thereby reduce cardiovascular risk. We examined whether voluntary wheel running in mice modulates cholesterol and bile acid metabolism. Methods: Male mice (10 wk old) were randomly assigned to have access to a voluntary running wheel for 2 wk (RUN group) or remained sedentary (SED group). Running wheel activity was recorded daily. In a first experiment, fecal sterol outputs, fecal bile acid profiles, plasma parameters, and expression levels of genes involved in cholesterol and bile acid metabolism were determined. In a second experiment, bile flow, biliary bile acid profile, and biliary secretion rates of cholesterol, phospholipids, and bile acids were determined. Results: The RUN group ran an average of 10 km.d(-1) and displayed lower plasma cholesterol compared with SED (P = 0.030). Fecal bile acid loss was induced by similar to 30% in running mice compared with SED (P = 0.0012). A similar to 30% increase in fecal cholesterol output in RUN (P = 0.014) was consistent with changes in parameters of cholesterol absorption, such as reduced plasma plant sterol-cholesterol ratio (P = 0.044) and decreased jejunal expression of Npc1l1 (P = 0.013). Supportive of an increased cholesterol synthesis to compensate for fecal sterol loss were increased hepatic mRNA levels of HMGCoA reductase (P = 0.006) and an increased plasma lathosterol-cholesterol ratio (P = 0.0011) in RUN. Conclusions: Voluntary wheel running increased cholesterol turnover in healthy mice owing to an increased fecal bile acid excretion and a decreased intestinal cholesterol absorption. Enhanced cholesterol turnover may contribute to the established reduction of cardiovascular risk induced by regular exercise

Variable effects of anti-diabetic drugs in animal models of myocardial ischemia and remodeling:A translational perspective for the cardiologist

<p>Diabetes and heart failure are very prevalent, and affect each other's incidence and severity. Novel therapies to reduce post-myocardial infarction (MI) remodeling that progresses into heart failure are urgently needed, especially in diabetic patients. Clinical studies have suggested that some oral anti-diabetic agents like metformin exert cardiovascular protective effects in heart failure patients with diabetes, whereas other agents may be deleterious. In the current review, we provide an overview of the cardio-specific effects of oral anti-diabetic drugs in animal models of acute MI, post-MI remodeling, and heart failure. Metformin has consistently been shown to ameliorate cardiac remodeling after ischemia/reperfusion (I/R) injury, as well as in several models of heart failure. Sulfonylurea derivatives are controversial with respect to their direct effects on the cardiovascular system. Thiazolidinediones protect against myocardial I/R injury, but their effects on post-MI remodeling are less clear and clinical studies raised concerns about their cardiovascular safety. Glucagon-like peptide-1 analogs have potential beneficial effects on the cardiovascular system that require further confirmation, whereas the results with dipeptidyl peptidase-4 inhibitors are equivocal. Current clinical guidelines, in the absence of prospective clinical trials that evaluated if certain oral anti-diabetic agents are superior over others, only provide generic recommendations, and do not take into account interesting experimental and mechanistic data. The available experimental evidence indicates that some anti-diabetic agents should be preferred over others if cardio-protective effects are warranted. These experimental clues need to be confirmed by clinical trials. (C) 2013 Elsevier Ireland Ltd. All rights reserved.</p>

Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice

AbstractObjectiveRegular physical activity decreases the risk for atherosclerosis but underlying mechanisms are not fully understood. We questioned whether voluntary wheel running provokes specific modulations in cholesterol turnover that translate into a decreased atherosclerotic burden in hypercholesterolemic mice.MethodsMale LDLR-deficient mice (8 weeks old) had either access to a voluntary running wheel for 12 weeks (RUN) or remained sedentary (CONTROL). Both groups were fed a western-type/high cholesterol diet. Running activity and food intake were recorded. At 12 weeks of intervention, feces, bile and plasma were collected to determine fecal, biliary and plasma parameters of cholesterol metabolism and plasma cytokines. Atherosclerotic lesion size was determined in the aortic root.ResultsRUN weighed less (∼13%) while food consumption was increased by 17% (p=0.004). Plasma cholesterol levels were decreased by 12% (p=0.035) and plasma levels of pro-atherogenic lipoproteins decreased in RUN compared to control. Running modulated cholesterol catabolism by enhancing cholesterol turnover: RUN displayed an increased biliary bile acid secretion (68%, p=0.007) and increased fecal bile acid (93%, p=0.009) and neutral sterol (33%, p=0.002) outputs compared to control indicating that reverse cholesterol transport was increased in RUN. Importantly, aortic lesion size was decreased by ∼33% in RUN (p=0.033).ConclusionVoluntary wheel running reduces atherosclerotic burden in hypercholesterolemic mice. An increased cholesterol turnover, specifically its conversion into bile acids, may underlie the beneficial effect of voluntary exercise in mice