Postinfarction exercise training alleviates cardiac dysfunction and adverse remodeling via mitochondrial biogenesis and SIRT1/PGC-1α/PI3K/Akt signaling

Exercise training mitigates cardiac pathological remodeling and dysfunction caused by myocardial infarction (MI), but its underlying cellular and molecular mechanisms remain elusive. Our present study in an in vivo rat model of MI determined the impact of post-MI exercise training on myocardial fibrosis, mitochondrial biogenesis, antioxidant capacity, and ventricular function. Adult male rats were randomized into: (a) Sedentary control group; (b) 4-week treadmill exercise training group; (c) Sham surgery group; (d) MI group with permanent ligation of left anterior descending coronary artery and kept sedentary during post-MI period; and (e) post-MI 4-week exercise training group. Results indicated that exercise training significantly improved post-MI left ventricular function and reduced markers of cardiac fibrosis. Exercise training also significantly attenuated MI-induced mitochondrial damage and oxidative stress, which were associated with enhanced antioxidant enzyme expression and/or activity and total antioxidant capacity in the heart. Interestingly, the adaptive activation of the SIRT1/PGC-1α/PI3K/Akt signaling following MI was further enhanced by post-MI exercise training, which is likely responsible for exercise-induced cardioprotection and mitochondrial biogenesis. In conclusion, this study has provided novel evidence on the activation of SIRT1/PGC-1α/PI3K/Akt pathway, which may mediate exercise-induced cardioprotection through reduction of cardiac fibrosis and oxidative stress, as well as improvement of mitochondrial integrity and biogenesis in post-MI myocardium.     

Overexpression of apolipoprotein-B improves cardiac function and increases survival in mice with myocardial infarction

Background

The heart produces apolipoprotein-B containing lipoproteins (apoB) whose function is not well understood. The aim of this study was to evaluate importance of myocardial apoB for cardiac function, structure and survival in myocardial infarction (MI) and heart failure (HF).

Methods and results

MI was induced in mice (n = 137) and myocardial apoB content was measured at 30 min, 3, 6, 24, 48, 120 h and 8 weeks post-MI. Transgenic mice overexpressing apoB (n = 27) and genetically matched controls (n = 27) were used to study the effects of myocardial apoB on cardiac function, remodeling, arrhythmias and survival after MI. Echocardiography was performed at rest and stress conditions at baseline, 2, 4 and 6 week post-MI and cumulative survival rate was registered. The myocardial apoB content increased both in the injured and the remote myocardium (p < 0.05) in response to ischemic injury. ApoB mice had 2-fold higher survival rate (p < 0.05) and better systolic function (p < 0.05) post-MI.

Conclusion

Overexpression of apoB in the heart increases survival and improves cardiac function after acute MI. Myocardial apoB may be an important cardioprotective system in settings such as myocardial ischemia and HF.     

Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling

After myocardial infarction (MI), there is progressive left ventricular (LV) remodeling and impaired exercise capacity. We tested the hypothesis that LV remodeling results in structural and functional changes that determine exercise impairment post-MI. Rats underwent coronary artery ligation (n = 12) or sham (n = 11) surgery followed by serial exercise tests and echocardiography for 16 wk post-MI. LV pressure-volume relationships were determined using a blood-perfused Langendorff preparation. Exercise capacity was 60% of shams immediately post-MI (P < 0.05) followed by a recovery to near normal during weeks 5-8. Thereafter, there was a progressive decline in exercise capacity to +/-40% of shams (P < 0.01). At both 8 and 16 wk post-MI, fractional shortening (FS) was reduced and end-diastolic diameter (EDD) was increased (P < 0.01). However, neither FS nor EDD correlated with exercise at 8 or 16 wk (r(2) < 0.12, P > 0.30). LV septal wall thickness was increased at both 8 (P = 0.17 vs. shams) and 16 wk (P = 0.035 vs. shams) post-MI and correlated with exercise at both times (r(2) >/= 0.50 and P 相似文献   

Cardiac Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase Causes Adverse Myocardial Remodeling following Myocardial Infarction

The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.     

Treadmill exercise reduces obestatin concentrations in rat fundus and small intestine

Ghrelin and obestatin both are orexigenic/anorexigenic peptides which are secreted from gastrointestinal tracts (fundus submucosa cells). Obestatin is a 23 amino acid peptide recently isolated from rat stomach, is encoded by the same gene that encodes ghrelin. It has been suggested that ghrelin/obestatin stimulate growth hormone release and have opposite actions on food intake. Distribution and biological activity of obestatin and its role in energy balance were studied in rodents. The purpose of the present study was to investigate fundus and intestine obestatin concentrations and selected hormonal responses to a treadmill exercise running program. Fourteen adult Wistar male rats (12-14 weeks old, 235-250 g) were used for this study. Animals were divided into control (n = 7) and training (n = 7) groups. Training group was given exercise on a motor-driven treadmill at 25 m/min (0% grade) for 60 min/day, 5 days/week for 6 weeks. Rats were sacrificed 48 h after the last session of exercise fundus, small intestine, and liver were excised, immediately washed in ice-cold saline, and frozen in liquid nitrogen for determination of obestatin and ATP concentrations and liver glycogen content. Plasma was collected for glucose, growth hormone (GH), insulin, and cortisol measurements. Total obestatin concentrations were significantly (P < 0.045, P < 0.032, respectively) low in trained rat fundus and intestine at rest. Fundus and intestine ATP content remained unchanged. Liver glycogen content was significantly (P < 0.039) higher in trained rats. Changes in plasma total obestatin, glucose, insulin, cortisol levels were not significant. Plasma GH concentrations was significantly (P < 0.001) higher in trained animals when compared with control rats. The data indicate that moderate treadmill exercise was able to reduce fundus and small intestine total obestatin concentrations and this reduction was accompanied with a higher plasma GH and liver glycogen content in trained rats. Exercise training might modulate fundus and intestine total obestatin levels via an improvement of energy source and a negative feedback action of GH on this peptide.     

Reduction of heart rate by chronic beta1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart

Adequate growth of coronary vasculature in the remaining left ventricular (LV) myocardium after myocardial infarction (post-MI) is a crucial factor for myocyte survival and performance. We previously demonstrated that post-MI coronary angiogenesis can be stimulated by bradycardia induced with the ATP-sensitive K(+) channel antagonist alinidine. In this study, we tested the hypothesis that heart rate reduction with beta-blockade may also induce coronary growth in the post-MI heart. Transmural MI was induced in 12-mo-old male Sprague-Dawley rats by occlusion of the left anterior descending coronary artery. Bradycardia was induced by administration of the beta-adrenoceptor blocker atenolol (AT) via drinking water (30 mg/day). Three groups of rats were compared: 1) control/sham (C/SH), 2) MI, and 3) MI + AT. In the MI + AT rats, heart rate was consistently reduced by 25-28% compared with C/SH rats. At 4 wk after left anterior descending coronary ligation, infarct size was similar in MI and MI + AT rats (67.1 and 61.5%, respectively), whereas a greater ventricular hypertrophy occurred in bradycardic rats, as indicated by a higher ventricular weight-to-body weight ratio (3.4 +/- 0.1 vs. 2.8 +/- 0.1 mg/g in MI rats). Analysis of LV function revealed a smaller drop in ejection fraction in the MI + AT than in the MI group ( approximately 24 vs. approximately 35%). Furthermore, in MI + AT rats, maximal coronary conductance and coronary perfusion reserve were significantly improved compared with the MI group. The better myocardial perfusion indexes in MI + AT rats were associated with a greater increase in arteriolar length density than in the MI group. Thus chronic reduction of heart rate induced with beta-selective blockade promotes growth of coronary arterioles and, thereby, facilitates regional myocardial perfusion in post-MI hearts.     

Moderate exercise training does not worsen left ventricle remodeling and function in untreated severe hypertensive rats.

Exercise training and hypertension induced cardiac hypertrophy but modulate differently left ventricle (LV) function. This study set out to evaluate cardiac adaptations induced by moderate exercise training in normotensive and untreated severe hypertensive rats. Four groups of animals were studied: normotensive (Ctl) and severe hypertensive (HT) Wistar rats were assigned to be sedentary (Sed) or perform a moderate exercise training (Ex) over a 10-wk period. Severe hypertension was induced in rat by a two-kidney, one-clip model. At the end of the training period, hemodynamic parameters and LV morphology and function were assessed using catheterism and conventional pulsed Doppler echocardiography. LV histology was performed to study fibrosis infiltrations. Severe hypertension increased systolic blood pressure to 202 +/- 9 mmHg and induced pathological hypertrophy (LV hypertrophy index was 0.34 +/- 0.02 vs. 0.44 +/- 0.02 in Ctl-Sed and HT-Sed groups, respectively) with LV relaxation alteration (early-to-atrial wave ratio = 2.02 +/- 0.11 vs. 1.63 +/- 0.12). Blood pressure was not altered by exercise training, but arterial stiffness was reduced in trained hypertensive rats (pulse pressure was 75 +/- 7 vs. 62 +/- 3 mmHg in HT-Sed and HT-Ex groups, respectively). Exercise training induced eccentric hypertrophy in both Ex groups by increasing LV cavity without alteration of LV systolic function. However, LV hypertrophy index was significantly decreased in normotensive rats only (0.34 +/- 0.02 vs. 0.30 +/- 0.02 in Ctl-Sed and Ctl-Ex groups, respectively). Moreover, exercise training improved LV passive filling in Ctl-Ex rats but not in Ht-Ex rats. In this study, exercise training did not reduce blood pressure and induced an additional physiological hypertrophy in untreated HT rats, which was slightly blunted when compared with Ctl rats. However, cardiac function was not worsened by exercise training.     

Influence of gender on the response to hemodynamic overload after myocardial infarction

After myocardial infarction (MI), the left ventricle (LV) undergoes ventricular remodeling characterized by progressive global dilation, infarct expansion, and compensatory hypertrophy of the noninfarcted myocardium. Little attention has been given to the response of remodeling myocardium to additional hemodynamic overload. Studies have indicated that gender may influence remodeling and the response to both MI and hemodynamic overload. We therefore determined 1) structural and function consequences of superimposing hemodynamic overload (systemic hypertension) on remodeling myocardium after a MI and 2) the potential influence of gender on this remodeling response. Male and female Dahl salt-sensitive and salt-resistant rats underwent coronary ligation, resulting in similar degrees of MI. One week post-MI, all rats were placed on a high-salt diet. Four groups were then studied 4 wk after initiation of high-salt feeding: MI female, MI female + hypertension, MI male, and MI male + hypertension. Hypertension-induced pressure overload resulted in additional comparable degrees of myocardial hypertrophy in both females and males. In females, hypertension post-MI resulted in concentric hypertrophy with no additional cavity dilation and no measurable scar thinning. In contrast, in males, hypertension post-MI resulted in eccentric hypertrophy, further LV cavity dilation, and scar thinning. Physiologically, concentric hypertrophy in post-MI hypertensive females resulted in elevated contractile function, whereas eccentrically hypertrophied males had no such increase. Female gender influences favorably the remodeling and physiological response to hemodynamic overload after large MI.     

Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart

We tested the hypothesis that left ventricular (LV) remodeling late after myocardial infarction (MI) is associated with myocyte apoptosis in myocardium remote from the infarcted area and is related temporally to LV dilation and contractile dysfunction. One, four, and six months after MI caused by coronary artery ligation, LV volume and contractile function were determined using an isovolumic balloon-in-LV Langendorff technique. Apoptosis and nuclear morphology were determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and Hoechst 33258 staining. Progressive LV dilation 1-6 mo post-MI was associated with reduced peak LV developed pressure (LVDP). In myocardium remote from the infarct, there was increased wall thickness and expression of atrial natriuretic peptide mRNA consistent with reactive hypertrophy. There was a progressive increase in the number of TUNEL-positive myocytes from 1 to 6 mo post-MI (2.9-fold increase at 6 mo; P < 0. 001 vs. sham). Thus LV remodeling late post-MI is associated with increased apoptosis in myocardium remote from the area of ischemic injury. The frequency of apoptosis is related to the severity of LV dysfunction.     

Effects of hydrogel injection on borderzone contractility post-myocardial infarction

Injectable hydrogels are a potential therapy for mitigating adverse left ventricular (LV) remodeling after myocardial infarction (MI). Previous studies using magnetic resonance imaging (MRI) have shown that hydrogel treatment improves systolic strain in the borderzone (BZ) region surrounding the infarct. However, the corresponding contractile properties of the BZ myocardium are still unknown. The goal of the current study was to quantify the in vivo contractile properties of the BZ myocardium post-MI in an ovine model treated with an injectable hydrogel. Contractile properties were determined 8 weeks following posterolateral MI by minimizing the difference between in vivo strains and volume calculated from MRI and finite element model predicted strains and volume. This was accomplished by using a combination of MRI, catheterization, finite element modeling, and numerical optimization. Results show contractility in the BZ of animals treated with hydrogel injection was significantly higher than untreated controls. End-systolic (ES) fiber stress was also greatly reduced in the BZ of treated animals. The passive stiffness of the treated infarct region was found to be greater than the untreated control. Additionally, the wall thickness in the infarct and BZ regions was found to be significantly higher in the treated animals. Treatment with hydrogel injection significantly improved BZ function and reduced LV remodeling, via altered MI properties. These changes are linked to a reduction in the ES fiber stress in the BZ myocardium surrounding the infarct. The current results imply that injectable hydrogels could be a viable therapy for maintaining LV function post-MI.     

Deficiency of Ataxia Telangiectasia Mutated Kinase Modulates Cardiac Remodeling Following Myocardial Infarction: Involvement in Fibrosis and Apoptosis

Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model. Methods and Results: Left ventricular (LV) structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.     

Effect of atorvastatin on expression of IL-10 and TNF-α mRNA in myocardial ischemia-reperfusion injury in rats

Myocardial ischemia and reperfusion (MI/R) is associated with an intense inflammatory reaction, which may lead to myocyte injury. Because statins protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering, we hypothesized that the protective effect of statins was related to the expression of TNF-alpha (TNF-α) and interleukin-10 (IL-10) mRNA. Seventy-two rats were randomly divided into three groups as follows: sham, I/R and I/R + atorvastatin. Atorvastatin (20 mg kg⁻¹ day⁻¹) treatment was administered daily via oral gavage to rats for 2, 7 or 14 days. Ischemia was induced via a 30-min coronary occlusion. Reperfusion was allowed until 2, 7 or 14 days while atorvastatin treatment continued. We measured infarct size, hemodynamics and the plasma levels and the mRNA expression of TNF-α and IL-10 in the three groups. We demonstrated that the up-regulation of expression of both TNF-α mRNA and IL-10 mRNA was associated the increased plasma levels of TNF-α and IL-10 in the ischemic and reperfused myocardium compared with that in the sham group (P < 0.01). Atorvastatin treatment prevented ischemia-reperfusion-induced up-regulation of both TNF-α and IL-10 mRNA, and improved left ventricular function (P < 0.01). Our findings suggested that atorvastatin may attenuate MI/R and better recovery of left ventricle function following ischemia and reperfusion and IL-10 was not directly likely involved in this protective mechanism.     

Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling

The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP(+/-)), and wild type. Post-MI survival was reduced with MT1-MMPexp and increased with MT1-MMP(+/-) compared with WT. LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT post-MI and was higher in the MT1-MMP(+/-) mice. In vivo localization of MT1-MMP using antibody-conjugated microbubbles revealed higher MT1-MMP levels post-MI, which were the highest in the MT1-MMPexp group and the lowest in the MT1-MMP(+/-) group. LV collagen content within the MI region was higher in the MT1-MMPexp vs. WT post-MI and reduced in the MT1-MMP(+/-) group. Furthermore, it was demonstrated that MT1-MMP proteolytically processed the profibrotic molecule, latency-associated transforming growth factor-1-binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by over fourfold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP(+/-) group, which was directionally paralleled by phospho-Smad-3 levels, a critical signaling component of the profibrotic transforming growth factor pathway. We conclude that modulating myocardial MT1-MMP levels affected LV function and matrix structure, and a contributory mechanism for these effects is through processing of profibrotic signaling molecules. These findings underscore the diversity of biological effects of certain MMP types on the LV remodeling process.     

TPPU enhanced exercise‐induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction

Exercise training (ET) is a safe and efficacious therapeutic approach for myocardial infarction (MI). Given the numerous benefits of exercise, exercise‐induced mediators may be promising treatment targets for MI. C57BL/6 mice were fed 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidine‐4‐yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHI), to increase epoxyeicosatrienoic acid (EET) levels, for 1 week before undergoing MI surgery. After 1‐week recovery, the mice followed a prescribed exercise programme. Bone marrow‐derived endothelial progenitor cells (EPCs) were isolated from the mice after 4 weeks of exercise and cultured for 7 days. Angiogenesis around the ischaemic area, EPC functions, and the expression of microRNA‐126 (miR‐126) and its target gene Spred1 were measured. The results were confirmed in vitro by adding TPPU to EPC culture medium. ET significantly increased serum EET levels and promoted angiogenesis after MI. TPPU enhanced the effects of ET to reduce the infarct area and improve cardiac function after MI. ET increased EPC function and miR‐126 expression, which were further enhanced by TPPU, while Spred1 expression was significantly down‐regulated. Additionally, the protein kinase B/glycogen synthase kinase 3β (AKT/GSK3β) signalling pathway was activated after the administration of TPPU. EETs are a potential mediator of exercise‐induced cardioprotection in mice after MI. TPPU enhances exercise‐induced cardiac recovery in mice after MI by increasing EET levels and promoting angiogenesis around the ischaemic area.     

Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice

There are conflicting data about gender differences in cardiac function after myocardial infarction (MI), including cardiac rupture and mortality. Using a mouse model of MI, we recently found that the cardiac rupture rate during the first week after MI was significantly lower in females than in males, suggesting that females have attenuated structural remodeling. Thus in this study, we attempted to determine whether: a) females have attenuated remodeling and faster healing during the early phase post-MI, and b) females have better cardiac function and outcome during the chronic phase compared to males. MI was induced in 12-week-old male and female C57BL/6J mice. Signs of early remodeling, including cardiac rupture, infarct expansion, inflammatory response, and collagen deposition, were studied during the first 2 weeks post-MI. Left ventricular remodeling and function were followed for 12 weeks post-MI. We found that males had a higher rate of cardiac rupture, occurring mainly at 3 to 5 days of MI and associated with a higher infarct expansion index. Neutrophil infiltration at the infarct border was more pronounced in males than females during the first days of MI, which were also characterized by increased MMP activity. However, the number of infiltrating macrophages was significantly higher in females at day 4. During the chronic phase post-MI, males had significantly poorer LV function, more prominent dilatation and significant myocyte hypertrophy compared to females. In conclusion, males have delayed myocardial healing, resulting in cardiac rupture, and the survivors have poorer cardiac function and pronounced maladaptive remodeling, whereas females show a better outcome during the development of HF.     

Exercise training intensity/volume affects plasma and tissue adiponectin concentrations in the male rat

The objective of the study was to determine the effects of exercise training intensity/volume on plasma total and high molecular weight (HMW) adiponectin and tissue total adiponectin concentrations. Thirty-two, eight week-old male Wistar rats (185 ± 5 g) were randomly assigned to one of four groups: high intensity (HI: 34 m/min ∼%80-%85 VO₂max), moderate intensity (MI: 28 m/min ∼%70-%75 VO₂max), low intensity (LI: 20m/min ∼ %50-%55 VO₂max), and sedentary control (SED). Experimental groups completed a 12-week exercise program of treadmill running at 0° slope, 1 h/day, 5 days/week. Since frequency and duration of exercise were identical among training groups, the volume of training was highest in the HI group followed by the MI and LI groups. Compared with SED animals, fasting plasma total and HMW adiponectin and adipose tissue total adiponectin concentrations were significantly higher in the HI and MI groups, but total adiponectin concentrations in liver and soleus muscle were not significantly lower than the SED rats. There were significantly lower plasma total testosterone levels in the HI group vs. SED group. Plasma total and HMW adiponectin were negatively correlated with HOMA-IR and insulin whereas total adiponectin was inversely related to TNF-α and HMW adiponectin was negatively correlated with total testosterone. Thus, data suggest there is a dose effect for exercise training intensity and accompanying volume for the adaptation of adipose tissue and circulating total and HMW adiponectin concentrations, whereas the changes of adiponectin concentrations in skeletal muscle and liver tissue may depend on the body's energy balance in the recovery period.     

Angiotensin AT2 receptor deficiency after myocardial infarction

Hearts of normotensive angiotensin II type 2 receptor (AT₂)-deficient mice do not develop fibrosis after angiotensin II-induced chronic hypertension. Thus, the goal of our study was to clarify whether AT₂ knockouts (KOs) are also characterized by altered left ventricular (LV) function and modified remodeling of the extracellular matrix (ECM) after induction of myocardial infarction (MI). MI was induced in 5-mo-old female AT₂-deficient mice and controls by occlusion of the left coronary artery. Time-matched sham-operated animals served as controls. After 48 h, the first sets of mice were hemodynamically characterized using a pressure-tip catheter (n=8/group). We also obtained pressure volume loops using a microconductance catheter in additional sets of animals 3 wk after induction of MI (n=7/group). Finally, the collagen index was illustrated by Sirius red staining and quantified by digital analysis. Whereas the LV function of sham-operated animals did not differ between both genotypes, the collagen index was 44% lower in KO animals. Forty-eight hours and 3 wk post-MI, systolic and diastolic LV function were impaired in both AT₂-deficient and wild-type (WT) animals to the same extent by approx 45%. No differences were found between the two genotypes with respect to LV hypertrophy and the fibrosis index in the infarcted and noninfarcted areas 3 wk post-MI. While AT₂-KO mice had less cardiac collagen content under basal conditions, the receptor deficiency had no significant influence on LV function at the two investigated time points after induction of MI or on the remodeling of ECM at the latter time point. Thus, hypetension-induced fibrosis is probably triggered by other control mechanisms than fibrosis induced by MI.     

Exercise improves adiponectin concentrations irrespective of the adiponectin gene polymorphisms SNP45 and the SNP276 in obese Korean women

The effects of exercise on adiponectin levels have been reported to be variable and may be attributable to an interaction between environmental and genetic factors. The single nucleotide polymorphisms (SNP) 45 (T > G) and SNP276 (G > T) of the adiponectin gene are associated with metabolic risk factors including adiponectin levels. We examined whether SNP45 and SNP276 would differentially influence the effect of exercise training in middle-aged women with uncomplicated obesity. We conducted a prospective study in the general community that included 90 Korean women (age 47.0 ± 5.1 years) with uncomplicated obesity. The intervention was aerobic exercise training for 3 months. Body composition, adiponectin levels, and other metabolic risk factors were measured. Prior to exercise training, only body weight differed among the SNP276 genotypes. Exercise training improved body composition, systolic blood pressure, maximal oxygen consumption, high-density lipoprotein cholesterol, and leptin levels. In addition, exercise improved adiponectin levels irrespective of weight gain or loss. However, after adjustments for age, BMI, body fat (%), and waist circumference, no differences were found in obesity-related characteristics (e.g., adiponectin) following exercise training among the SNP45 and the 276 genotypes. Our findings suggest that aerobic exercise affects adiponectin levels regardless of weight loss and this effect would not be influenced by SNP45 and SNP276 in the adiponectin gene.     

Serum MMP-8: A Novel Indicator of Left Ventricular Remodeling and Cardiac Outcome in Patients after Acute Myocardial Infarction

Objective

Left ventricular (LV) remodeling following myocardial infarction (MI) is characterized by progressive alterations of structure and function, named LV remodeling. Although several risk factors such as infarct size have been identified, LV remodeling remains difficult to predict in clinical practice. Changes within the extracellular matrix, involving matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are an integral part of left ventricular (LV) remodeling after myocardial infarction (MI). We investigated the temporal profile of circulating MMPs and TIMPs and their relations with LV remodeling at 1 year and clinical outcome at 3 years in post-MI patients.

Methods

This prospective multicentre study included 246 patients with a first anterior MI. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI, and analysed at a core laboratory. LV remodeling was defined as the percent change in LV end-diastolic volume (EDV) from baseline to 1 year. Serum samples were obtained at hospital discharge, 1, 3, and 12 months. Multiplex technology was used for analysis of MMP-1, -2, -3, -8, -9, -13, and TIMP-1, -2, -3, -4 serum levels.

Results

Baseline levels of MMP-8 and MMP-9 were positively associated with changes in LVEDV (P = 0.01 and 0.02, respectively). When adjusted for major baseline characteristics, MMP-8 levels remained an independent predictor LV remodeling (P = 0.025). By univariate analysis, there were positive relations between cardiovascular death or hospitalization for heart failure during the 3-year follow-up and the baseline levels of MMP-2 (P = 0.03), MMP-8 (P = 0.002), and MMP-9 (P = 0.03). By multivariate analysis, MMP-8 was the only MMP remaining significantly associated with clinical outcome (P = 0.02).

Conclusion

Baseline serum MMP-8 is a significant predictor of LV remodeling and cardiovascular outcome after MI and may help to improve risk stratification.     

Early moderate exercise benefits myocardial infarction healing via improvement of inflammation and ventricular remodelling in rats

Thus far, the cellular and molecular mechanisms related to early (especially within 24 hours after acute myocardial infarct (MI)) exercise‐mediated beneficial effects on MI have not yet been thoroughly established. In the present study, we demonstrated that acute MI rats that underwent early moderate exercise training beginning one day after MI showed no increase in mortality and displayed significant improvements in MI healing and ventricular remodelling, including an improvement in cardiac function, a decrease in infarct size, cardiomyocyte apoptosis, cardiac fibrosis and cardiomyocyte hypertrophy, and an increase in myocardial angiogenesis, left ventricular wall thickness and the number of cardiac telocytes in the border zone. Integrated miRNA‐mRNA profiling analysis performed by the ingenuity pathway analysis system revealed that the inhibition of the TGFB1 regulatory network, activation of leucocytes and migration of leucocytes into the infarct zone comprise the molecular mechanism underlying early moderate exercise‐mediated improvements in cardiac fibrosis and the pathological inflammatory response. The findings of the present study demonstrate that early moderate exercise training beginning one day after MI is safe and leads to significantly enhanced MI healing and ventricular remodelling. Understanding the mechanism behind the positive effects of this early training protocol will help us to further tailor suitable cardiac rehabilitation programmes for humans.