MicroRNA-122 aggravates angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts via the modulation of SIRT6-elabela-ACE2 signaling.

Abnormal aortic adventitial fibroblasts (AFs) play essential roles in the development of vascular remodeling and disorders. Previous studies revealed that microRNA-122 (miR-122) levels were elevated in the aortic adventitia of hypertensive rats with vascular injury. Here, we aim to evaluate the biological effects and underlying mechanisms of miR-122 in rat AFs. Exposure to angiotensin II (ATII) in rat AFs resulted in decreased levels of sirtuin 6 (SIRT6), elabela (ELA), and angiotensin-converting enzyme 2 (ACE2). Additionally, stimulation with ATII contributed to a decline in autophagic flux and obvious increases in cellular migration, oxidative stress, and apoptosis, which were exacerbated by the transfection of miR-122-5p mimic but were rescued by miR-122-5p inhibitor, exogenous replenishment of ELA, and recombinant adeno-associated virus expressing SIRT6 (rAAV-SIRT6), respectively. Moreover, stimulation with miR-122-5p mimic led to a marked reduction in the levels of SIRT6 and ELA in rat AFs, which were elevated by stimulation with rAAV-SIRT6. Furthermore, miR-122-5p inhibitor-mediated pro-autophagic, anti-oxidant and anti-apoptotic effects in rat AFs were partially suppressed by 3-methyladenine, SIRT6 small interfering RNA (siRNA) and ELA siRNA, which were linked with the downregulation in the protein levels of LC3-II, beclin-1, and ACE2 and the upregulation of p62 expression and bax/bcl-2 ratio. Our findings indicated that miR-122-5p inhibition prevented ATII-mediated loss of autophagy, and the promotion of apoptosis and oxidative stress via activating the SIRT6-ELA-ACE2 signaling. MiR-122-5p may be a novel predictive biomarker of adventitial injury, and targeting the SIRT6-ELA-ACE2 signaling may have the potential therapeutic importance of controlling vascular remodeling and disorders.

The association between orthostatic blood pressure changes and subclinical target organ damage in subjects over 60 years old.

BACKGROUND: Although recent studies have indicated that both orthostatic hypotension and orthostatic hypertension independently predict cardiovascular events, the underlying mechanisms are still controversial. The aim of the study was to investigate the relationships between orthostatic changes and organ damage in subjects over 60 years old. METHODS: This is a prospective observational cohort study. One thousand nine hundred and ninety-seven subjects over 60 years old were enrolled. Participants were grouped according to whether they had a drop ≥ 20 mmHg in systolic or ≥ 10 mmHg in diastolic BP (orthostatic hypotension), an increase in mean orthostatic systolic blood pressure ≥ 20 mm Hg (orthostatic hypertension), or normal changes within 3 min of orthostatism. Multiple regression modeling was used to investigate the relationship between orthostatic hypotension, orthostatic hypertension and subclinical organ damage with adjustment for confounders. RESULTS: Orthostatic hypotension and orthostatic hypertension were found in 461 (23.1%) and 189 (9.5%) participants, respectively. Measurement of carotid intima-media thickness (IMT), brachial-ankle pulse wave velocity (baPWV), clearance of creatinine, and microalbuminuria were associated with orthostatic hypotension; measurement of IMT and baPWV were associated with orthostatic hypertension in a cruse model. After adjustment, IMT [odds ratio (OR), 95% confidence interval (CI) per one-SD increment: 1.385, 1.052-1.823; P = 0.02], baPWV (OR = 1.627, 95% CI: 1.041-2.544; P = 0.033) and microalbuminuria (OR = 1.401, 95% CI: 1.002-1.958; P = 0.049) were still associated with orthostatic hypotension, while orthostatic hypertension was only associated with IMT (OR = 1.730, 95% CI: 1.143-2.618; P = 0.009). CONCLUSIONS: Orthostatic hypotension seems to be independently correlated with increased carotid atherosclerosis, arterial stiffness and renal damage in subjects over 60 years old. Orthostatic hypertension correlates with carotid atherosclerosis only.

Progress in Therapies for Myocardial Ischemia Reperfusion Injury.

BACKGROUND: Experimental studies of acute myocardial infarction have revealed that up to half of the final infarct size may be due to reperfusion injury rather than the initial ischemic incident. Research over the past three decades has deepened our understanding of the molecular mechanisms underlying ischemic reperfusion injury and several therapeutic strategies to decrease the incidence and severity of reperfusion injury have been explored. OBJECTIVE: To discuss the promising therapies and future perspectives on methods to attenuate myocardial reperfusion injury. RESULTS: Existing therapies that address reperfusion can be divided into two major groups comprising nonpharmacological and pharmacological interventions. Myriad pharmacological and nonpharmacological approaches to reduce lethal reperfusion injury have been employed. Although many initial clinical studies were negative, more recent proof-of-concept clinical trials are promising. To date, the most encouraging results are with ischemic postconditioning, remote ischemic preconditioning, ANP, adenosine, cyclosporine and exenatide. CONCLUSION: Studies demonstrate that nonpharmacological and pharmacological conditioning can be used together as part of a multifaceted approach to improve clinical outcomes in patients with ischemic heart disease.

Clinical Application of Induced Pluripotent Stem Cells in Cardiovascular Medicine.

Induced pluripotent stem cells (iPSCs) are generated by reprogramming human somatic cells through the overexpression of four transcription factors: Oct4, Sox2, Klf4 and c-Myc. iPSCs are capable of indefinite self-renewal, and they can differentiate into almost any type of cell in the body. These cells therefore offer a highly valuable therapeutic strategy for tissue repair and regeneration. Recent experimental and preclinical research has revealed their potential for cardiovascular disease diagnosis, drug screening and cellular replacement therapy. Nevertheless, significant challenges remain in terms of the development and clinical application of human iPSCs. Here, we review current progress in research related to patient-specific iPSCs for ex vivo modeling of cardiovascular disorders and drug screening, and explore the potential of human iPSCs for use in the field of cardiovascular regenerative medicine.

The ideal cardiovascular health metrics associated inversely with mortality from all causes and from cardiovascular diseases among adults in a Northern Chinese industrial city.

BACKGROUND AND AIMS: The American Heart Association has recently established seven ideal cardiovascular health metrics for cardiovascular health promotion and disease reduction (i.e., non-smoking, normal body mass index, physically active, healthy diet, and normal levels of cholesterol, blood pressure and fasting blood glucose). The present study seeks to evaluate how well these metrics predict mortality from all causes and cardiovascular diseases in adult Chinese living in a northern industrial city. METHODS AND RESULTS: Data of 95,429 adults who participated in the Kailuan cohort study from June 2006 to October 2007 was analyzed. All participants underwent questionnaire assessment, clinical examination, laboratory assessments and were followed up biannually. During a median follow-up of 4.02 years, 1,843 deaths occurred, with 597 deaths resulting from cardiovascular diseases. Lower mortality rates from all causes and cardiovascular diseases were observed among the subjects who met a higher number of the ideal health metrics. Compared to the participants who met none or one ideal health metric, those meeting ≥5 ideal health metrics had a lower risk of all-cause mortality by 30% (adjusted hazard ratio, 0.70; 95% confidence interval, 0.56-0.88) and a lower risk of mortality from cardiovascular diseases by 39% (adjusted hazard ratio, 0.61; 95% confidence interval, 0.41-0.89) . Four metrics (smoking status, physical activity, blood pressure and fasting blood glucose) were significantly associated with all-cause mortality. Three metrics (physical activity, blood pressure and fasting blood glucose) were significantly associated with mortality from cardiovascular diseases. CONCLUSION: The number of ideal health metrics is negatively associated with mortality rates from all causes and cardiovascular diseases among adults in a Northern Chinese industrial city. The data supports the AHA recommendation of ideal health metrics for adults from Northern China.

Downregulation of microRNA-19b contributes to angiotensin II-induced overexpression of connective tissue growth factor in cardiomyocytes.

OBJECTIVES: The present study was designed to decipher the molecular mechanisms underlying angiotensin (Ang) II-induced overexpression of connective tissue growth factor (CTGF) in cultured cardiomyocytes. METHODS: Cardiomyocytes isolated from 1- to 3-day-old neonatal rats were cultured and treated with 100 nM Ang II with or without pretreatment with 10 nM telmisartan, an Ang II type 1 receptor antagonist. The role of microRNA (miR)-19b in the regulation of Ang II-induced CTGF expression was evaluated in cultured cardiomyocytes with quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. RESULTS: We provide several lines of evidence to show that miR-19b contributes to the Ang II-induced overexpression of CTGF in cultured cardiomyocytes. Firstly, administration of Ang II decreased the level of miR-19b dramatically (p < 0.05 vs. control), which was abolished by telmisartan. Secondly, Ang II increased the level of CTGF significantly (p < 0.05 vs. control), which was also prevented by pretreatment with telmisartan. Thirdly, overexpression of miR-19b decreased CTGF levels (p < 0.05 vs. control). Finally, transfection of miR-19b into cardiomyocytes prevented the upregulation of CTGF induced by Ang II. CONCLUSION: Downregulation of miR-19b contributes to Ang II-induced overexpression of CTGF in cultured cardiomyocytes.

[Hyperglycemia at admission and outcome in elderly patients with acute ST segment elevation myocardial infarction underwent primary percutaneous coronary intervention].

OBJECTIVE: To investigate the association between hyperglycemia and outcome in elderly patients with acute ST segment elevation myocardial infarction (STEMI) underwent primary percutaneous coronary intervention (PCI). METHODS: This retrospective analysis was performed on 284 elderly patients (age > or = 60 years) with acute STEMI underwent primary PCI between January 2000 to April 2004 in our department. Patients were divided into 3 groups according to the level of blood glucose on admission: group A, < 7.8 mmol/L; group B, 7.8 - 10.9 mmol/L; group C, > or = 11.0 mmol/L. RESULTS: (1) The proportion of female in group B and group C was greater than that of group A (33.3% vs. 26.5%, P < 0.01; 40.2% vs. 26.5%, P < 0.01). The hospital stay time of group B and group C was significantly longer than that of group A (16.0 days vs. 13.9 days, P < 0.05; 16.6 days vs. 13.9 days, P < 0.05). There were more patients with history of hypertension in group C than that in group A (72.1% vs. 54.9%, P < 0.01). (2) After PCI, the proportion of patients with TIMI myocardial perfusion grade (TMPG) 0-1 in group B and C was greater than that of group A (22.6% vs. 13.3%, P < 0.05; 34.1% vs. 13.3%, P < 0.05). The proportion of patients with TMPG 3 in group B and C was less than that in group A (74.3% vs. 84.4%, P < 0.05; 57.6% vs. 84.4%, P < 0.05). The complication rate of PCI was significantly higher in group C than in group A (42.5% vs. 20.6%, P < 0.01) and group B (42.5% vs. 26.6%, P < 0.01). IABP use was significantly more in group C than that in group A (19.5% vs. 4.9%, P < 0.01) and group B (19.5% vs. 6.4%, P < 0.01). (3) There were more patients with grade of Killip class > or = 2 in group C than that in group A (44.8% vs. 23.5%, P < 0.01) and group B (44.8% vs. 27.7%, P < 0.01). The in-hospital mortality rate (8.0% vs. 1.1%, P < 0.05) and one-year mortality rate (18.7% vs. 3.4%, P < 0.05) of group C were significantly higher than those in group A. CONCLUSION: Hyperglycemia at admission was associated with poor tissue perfusion, cardiac function and prognosis in elderly patients with acute STEMI underwent primary PCI.

Relation of hyperglycemia to ST-segment resolution after primary percutaneous coronary intervention for acute myocardial infarction.

BACKGROUND: Hyperglycemia has been shown to be a powerful predictor of poor outcome after ST-segment elevation myocardial infarction (STEMI). This study aimed to evaluate the effect of admission glucose on microvascular flow after successful primary percutaneous coronary intervention (PCI) in patients with STEMI. METHODS: Successful primary PCI was performed in 267 patients with STEMI. The maximum ST elevation of single electrocardiogram (ECG) lead before and 60 minutes after PCI was measured, and patients were then divided into 3 groups according to the degree of ST-segment resolution (STR): absent (<30%), partial (30% to 70%) or complete (> or =70%). RESULTS: Of the 267 patients, 48 (18.0%) had absent STR, 137 (51.3%) experienced partial STR, and 82 (30.7%) had complete STR. The degree of STR decreased with increasing admission glucose levels (P=0.032), and patients with hyperglycemia (serum glucose level > or =11 mmol/L) were more likely to have absent STR (P=0.001). Moreover,hyperglycemia was an independent predictor of incomplete STR (odds ratio, 1.870; 95% confidence interval, 1.038 to 3.371, P=0.037). CONCLUSIONS: Hyperglycemia on admission is associated with abnormal coronary microvascular reperfusion in patients with STEMI after successful primary PCI, which may contribute, at least in part, to the poor outcomes in these patients.

[Effects of reperfusion arrhythmia on myocardial apoptosis and left ventricular remodeling in patients with acute myocardial infarction].

OBJECTIVE: To observe plasma soluble Fas/APO-1 concentration in patients with reperfusion arrhythmia immediately after coronary reperfusion in patients with acute myocardial infarction (AMI) and to investigate the impact of reperfusion arrhythmia on left ventricular (LV) remodeling in AMI patients. To observe the relationship between cardiomyocytes apoptosis with reperfusion arrhythmia in patients with acute myocardial infarction (AMI), and investigate the impact of reperfusion arrhythmia on left ventricular (LV) remodeling in patients with AMI. METHODS: One hundred and fifty-six patients with AMI who received reperfusion therapy were selected as subjects. Fifty-eight patients underwent reperfusion arrhythmia within 24 hour after coronary reperfusion treatment (RA group). Ninety-eight patients did not occurred reperfusion arrhythmia (Non-RA group). Strepavidin-biotin ELISA was used to determine the soluble Fas/APO-1 plasma concentration at baseline, 7 day (d) and 2 - 4 week (W). All patients were followed up with scheduled evaluations of LV function and morphology with left ventriculography for 1 year. RESULTS: 1. It was later that the coronary reperfusion occurred in patients of RA group than that of Non-RA group, and the left anterior descending was more frequent infarct related artery (60.3%) than of Non-RA group (36.9%, P < 0.05). 2. The Fas/APO-1 levels in patients of RA group higher than those of Non-RA group at baseline [(13.82 +/- 4.36) microg/L vs (8.19 +/- 3.56) microg/L, P < 0.01]. 3. The highest level of Fas/APO-1 was on 7 d after AMI and the plasma levels of Fas/APO-1 in 2 - 4 W were slightly lower than those in 7 d in the two groups [RA group: (10.91 +/- 3.65) microg/L vs (14.26 +/- 4.98) microg/L, P < 0.05; Non-RA group: (4.69 +/- 1.87) microg/L vs (12.19 +/- 3.25) microg/L, P < 0.01]. However, the Fas/APO-1 level of 2 - 4 W in RA group was slightly higher than the level in Non-RA group [(10.91 +/- 3.65) microg/L vs (4.69 +/- 1.87) microg/L, P < 0.01]. 4. There was on difference between two groups in left ventricular ejection fraction (LVEF) and the left ventricular end-diastolic dimension (LVEDD) one week after AMI [LVEF: (47.7 +/- 9.6)% vs (49.2 +/- 8.9)%, P > 0.05; LVEDD: (59.7 +/- 10.3) mm vs (57.4 +/- 12.4) mm, P > 0.05]. 5. In the Non-RA group, the LVEF significantly increased from 1 W phase to the 1-year phase [from (49.2 +/- 8.9)% to (59.5 +/- 9.2)%, P < 0.05], but unchanged in the 58 patients without reperfusion arrhythmia [from (47.7 +/- 9.6)% to (49.9 +/- 10.1)%, P > 0.05]. The LVEF of Non-RA group was slightly higher than that of RA group at 1 year [(59.5 +/- 9.2)% vs (49.9 +/- 10.1)%, P < 0.05]. The LVEDD had no significant difference between two groups, but there was downtrend in the Non-RA group at 1 year after AMI. CONCLUSION: Reperfusion arrhythmia was related with cardiomyocytes apoptosis in patients with AMI, and might influence left ventricular function and promote LV remodeling.

[Equivalent cardioprotective effect of "half-conditioning" and post-conditioning in a canine model of myocardial ischemia and reperfusion].

OBJECTIVE: To study the effects of "half-conditioning", a modified postconditioning process, on myocardial injury induced by severe myocardial ischemia/reperfusion (I/R) in anesthetized dogs. METHODS: Mongrel dogs of both sexes were subjected to 40 min ischemia (coronary blood flow reduced by 80% via controlled coronary stenosis). At the end of ischemia, dogs were randomly received one of the following treatments: (1) control, reperfusion for 3 h (n = 7); (2) post-conditioning, three cycles of ischemia 30 s followed by reperfusion for 30 s and then reperfusion for 3 h (n = 7); (3) half-conditioning, coronary blood flow recovered to 50% for 2 min, then 80% for 2 min, thereafter 100% for 3 h (n = 7). Electrocardiogram (ECG), arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Plasma creatine kinase (CK) and lactate dehydrogenase (LDH) activity were measured spectrophotometrically. Myocardial necrosis was defined by TTC-staining. RESULTS: Compared with control animals, arrhythmia incidence, LVEDP at 2 and 3 h reperfusion, CK and LDH were significantly reduced in animals received post-conditioning and half-conditioning treatments, infarct size as a percentage (%) of the area at risk was also significantly reduced by post-conditioning and half-conditioning treatments. No differences were observed in the post-conditioning and half-conditioning groups. CONCLUSION: Half-conditioning exerts the same cardioprotective effects on post-ischemic hearts as postconditioning.