Cardiac aging is associated with compromised myocardial function and morphology although the underlying mechanism remains elusive. ALDH2, an essential mitochondrial enzyme governing cardiac function, displays polymorphism in human. This study was designed to examine the role of ALDH2 in aging-induced myocardial anomalies. Myocardial mechanical and intracellular Ca2+ properties were examined in young (4–5 mo) and old (26–28 mo) wild-type (WT) and ALDH2 transgenic mice. Cardiac histology, mitochondrial integrity, O2− generation, apoptosis and signaling cascades including AMPK activation and Sirt1 level were evaluated. Myocardial function and intracellular Ca2+ handling were compromised with advanced aging, the effects were accentuated by ALDH2. H&E and Masson trichrome staining revealed cardiac hypertrophy and interstitial fibrosis associated with greater left ventricular mass and wall thickness in aged mice. ALDH2 accentuated aging-induced cardiac hypertrophy but not fibrosis. Aging promoted O2− release, apoptosis and mitochondrial injury (mitochondrial membrane potential, levels of UCP2 and PGC-1α), the effects were also exacerbated by ALDH2. Aging dampened AMPK phosphorylation and Sirt1, the effects of which were exaggerated by ALDH2. Treatment of the ALDH2 activator Alda-1 accentuated aging-induced O2− generation and mechanical dysfunction in cardiomyocytes, the effects of which were mitigated by co-treatment with activators of AMPK and Sirt1 AICAR, resveratrol and SRT1720. Examination of human longevity revealed a positive correlation between lifespan and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may accentuate myocardial remodeling and contractile dysfunction in aging possibly through AMPK/Sirt1-mediated mitochondrial injury.
Naoxintong (NXT) is a Chinese Materia Medica standardized product extracted from 16 various kinds of Chinese traditional herbal medicines including Salvia miltiorrhiza, Angelica sinensis, Astragali Radix. Naoxintong is clinically effective in treating ischaemia heart disease. Nucleotide‐binding oligomerization domain‐Like Receptor with a Pyrin domain 3 (NLRP3) inflammasome has been critically involved in myocardial ischaemia/reperfusion (I/R) injury. Here, we have been suggested that NXT might attenuate myocardial I/R injury via suppression of NLRP3 inflammasome activation. Male C57BL6 mice were subjected to myocardial I/R injury via 45 min. coronary ligation and release for the indicated times. Naoxintong (0.7 g/kg/day) and PBS were orally administrated for 2 weeks before surgery. Cardiac function assessed by echocardiography was significantly improved in the NXT group compared to PBS group at day 2 after myocardial I/R. NLRP3 inflammasome activation is crucially involved in the initial inflammatory response after myocardial I/R injury, leading to cleaved caspase‐1, mature interleukin (IL)‐1β production, accompanying by macrophage and neutrophil infiltration. The cardioprotective effect of NXT was associated with a diminished NLRP3 inflammasome activation, decreased pro‐inflammatory macrophage (M1 macrophages) and neutrophil infiltration after myocardial I/R injury. In addition, serum levels of IL‐1β, indicators of NLRP3 inflammasome activation, were also significantly suppressed in the NXT treated group after I/R injury. Naoxintong exerts cardioprotive effects at least partly by suppression of NLRP3 inflammasome activation in this I/R injury model.
Atherosclerotic cardiovascular disease is a common and severe complication of diabetes. There is a large need to identify the effective and safety strategies on diabetic cardiovascular disease (DCVD). 9-PAHSA is a novel endogenous fatty acid, and has been reported to reduce blood glucose levels and attenuate inflammation. We aim to evaluate the effects of 9-PAHSA on DCVD and investigate the possible mechanisms underlying it. Firstly, serum 9-PAHSA levels in human were detected by HPLC-MS/MS analysis. Then 9-PAHSA was synthesized and purified. The synthesized 9-PAHSA was gavaged to db/db mice with 50 mg/kg for 4 weeks. The carotid arterial plaque and cardiac structure was assessed by ultrasound. Cardiac autophagy was tested by western blot analysis, electron microscope and iTRAQ. The results showed that 9-PAHSA, in patients with type 2 diabetes mellitus (T2DM), was significantly lower than that in non-diabetic subjects. Administration of 9-PAHSA for 2 weeks reduced blood glucose levels. Ultrasound observed that continue administration of 9-PAHSA for 4 weeks ameliorated carotid vascular calcification, and attenuated myocardial hypertrophy and dysfunction in db/db mice. Electron microscopy showed continue 9-PAHSA treatment significantly increased autolysosomes, while dramatically decreased greases in the myocardial cells of the db/db mice. Moreover, iTRAQ analysis exhibited that continue 9-PAHSA treatment upregulated BAG3 and HSPB8. Furthermore, western blot analysis confirmed that 9-PAHSA down-regulated Akt/mTOR and activated PI3KIII/BECN1 complex in diabetic myocardium. Thus, 9-PAHSA benefits DCVD in diabetic mice by ameliorating carotid vascular calcification, promoting autophagic flux and reducing myocardial hypertrophy.
This study aims to systematically reveal the changes in protein levels induced by regular exercise in mice with ischemic-induced heart failure (HF). Aerobic exercise training for the ischemic-induced HF mice lasted for 4 weeks and then we used the liquid chromatography-mass spectrometry method to identify and quantify the protein profile in the myocardium of mice. As a whole, 1,304 proteins (597 proteins up-regulated; 707 proteins down-regulated) were differentially expressed between the exercise group and the sedentary group, including numerous proteins related to energy metabolism. The significant alteration of the component (E1 component subunit alpha and subunit beta) and the activity-regulating enzyme (pyruvate dehydrogenase kinase 2 and pyruvate dehydrogenase kinase 4) of pyruvate dehydrogenase complex and poly [ADP-ribose] polymerase 3, a nicotinamide adenine dinucleotide(+)-consuming enzymes, was further verified in targeted analysis. Generally, this proteomics profiling furnishes a systematic insight of the influence of aerobic exercise on HF.
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