Rationale: Exercise training, in addition to reducing cardiovascular risk factors, confers direct protection against myocardial ischemia/reperfusion injury and has been associated with improved heart attack survival in humans. However, the underlying mechanisms of exercise-afforded cardioprotection are still unclear. Objective: To investigate the role of exercise-derived circulating exosomes in cardioprotection and the molecular mechanisms involved. Methods and Results: Circulating exosomes were isolated from the plasma of volunteers with or without exercise training and rats subjected to 4-week swim exercise or sedentary littermates 24 hours after the last training session. Although the total circulating exosome level did not change significantly in exercised subjects 24 hours post-exercise compared with the sedentary control, the isolated plasma exosomes from exercised rats afforded remarkable protection against myocardial ischemia/reperfusion injury. miRNA sequencing combined with quantitative reverse transcription polymerase chain reaction validation identified 12 differentially expressed miRNAs from the circulating exosomes of exercised rats, among which miR-342-5p stood out as the most potent cardioprotective molecule. Importantly, the cardioprotective effects and the elevation of exosomal miR-342-5p were also observed in exercise-trained human volunteers. Moreover, inhibition of miR-342-5p significantly blunted the protective effects of exercise-derived circulating exosomes in hypoxia/reoxygenation cardiomyocytes; in vivo cardiac-specific inhibition of miR-342-5p through serotype 9 adeno-associated virus–mediated gene delivery attenuated exercise-afforded cardioprotection in myocardial ischemia/reperfusion rats. Mechanistically, miR-342-5p inhibited hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting Caspase 9 and Jnk2 ; it also enhanced survival signaling (p-Akt) via targeting phosphatase gene Ppm1f . Of note, exercise training or laminar shear stress directly enhanced the synthesis of miR-342-5p in endothelial cells. Conclusions: Our findings reveal a novel endogenous cardioprotective mechanism that long-term exercise-derived circulating exosomes protect the heart against myocardial ischemia/reperfusion injury via exosomal miR-342-5p.

Background Exercise benefits to cardiac rehabilitation (CR) following stable myocardial infarction (MI). The suitable exercise duration for aged patients with coronary heart disease (CHD) remains controversial, and the underlying molecular mechanism is still unclear. Methods and Results 18-Month-old mice after stable MI were randomly submitted to different durations of exercise, including 15 and 60 min swimming training (ST) once per day, five times a week for 8 weeks. Compared to sedentary mice, 15 min ST, rather than 60 min ST, significantly augmented left ventricular function, increased survival rate, and suppressed myocardial fibrosis and apoptosis. 15 min ST improved mitochondrial morphology via regulating mitochondrial fission-fusion signaling. 15 min ST regulated mitophagy signaling via inhibiting LC3-II and P62 levels and increasing PINK/Parkin expression. 15 min ST also inhibited ROS production and enhanced antioxidant SOD2 activity. Notably, 15 min ST significantly increased sirtuin (SIRT) 3 level (2.7-fold) in vivo while the inhibition of SIRT3 exacerbated senescent H9c2 cellular LDH release and ROS production under hypoxia. In addition, SIRT3 silencing impairs mitochondrial dynamics and mitophagy in senescent cardiomyocytes against simulated ischemia (SI) injury. Conclusion Collectively, our study demonstrated for the first time that sustained short-duration exercise, rather than long-duration exercise, attenuates cardiac dysfunction after MI in aged mice. It is likely that the positive regulation induced by a short-duration ST regimen on the elevated SIRT3 protein level improved mitochondrial quality control and decreased apoptosis and fibrosis contributed to the observed more resistant phenotype.

Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exerciseinduced alleviation of hypertension in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 305: H1111-H1119, 2013. First published August 2, 2013; doi:10.1152/ajpheart.00290.2013.-Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-ofloading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/ endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/ eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exerciseenhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension.hypertension; GRK2; vascular insulin resistance; exercise HYPERTENSION, DEFINED AS blood pressure (BP) at or above 140 mmHg systolic and/or 90 mmHg diastolic, remains one of the most significant modifiable risk factors for cardiovascular diseases, including coronary artery disease, stroke, and heart failure. Although several studies report controversial relationships between BP and physical activity, meta-analysis of randomized controlled trials shows chronic dynamic aerobic endurance training reduces BP (5). Therefore, regular physical exercise is broadly recommended by current European and American hypertension guidelines as first-line therapy. Endurance training decreases BP, in part, through red...

These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF.

The present study was conducted to explore the effects of a purified tartary buckwheat flavonoid fraction (TBF) on insulin resistance and hepatic oxidative stress in mice fed high fructose in drinking water (20%) for 8 weeks. The results indicated that continuous administration of TBF dose-dependently improved the insulin sensitivity and glucose intolerance in high fructose-fed mice. TBF treatment also reversed the reduced level of insulin action on the phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (Akt) and phosphatidylinositol 3-kinase (PI3K), as well as the translocation of glucose transporter type 4 (GLUT4) in the insulin-resistant liver. Furthermore, TBF was found to exert high antioxidant capacity as it acts as a shield against oxidative stress induced by high fructose by restoring the antioxidant status, and modulating nuclear factor E2 related factor 2 (Nrf2) translocation to the nucleus with subsequently up-regulated antioxidative enzyme protein expression. Histopathological examinations revealed that impaired pancreatic/hepatic tissues were effectively restored in high fructose-fed mice following TBF treatment. Our results show that TBF intake is effective in preventing the conversion of high fructose-induced insulin resistance and hepatic oxidative stress in mice by improving the insulin signaling molecules and the Nrf2 signal pathway in the liver.