Oxidized low-density lipoprotein (ox-LDL) can induce vascular smooth muscle cell (VSMC) proliferation and differentiation, which is the important mechanism of the pro-atherogenic effects of ox-LDL. Although miRNAs are crucial regulators of the ox-LDL effects on VSMC, the detailed mechanisms are not fully elucidated. So, we investigated the miRNAs changes in the proliferation of human coronary artery smooth muscle cells (hCASMCs) induced by ox-LDL and the functional significance of some miRNAs, which were regulated significantly. Using miRNA microarray, real-time PCR, and luciferase reporter assay, our study showed that miR-490-3p and insulin-like growth factor-1 (IGF1) expression were down-regulated, whereas pregnancy-associated plasma protein A (PAPP-A) and IGF2 expression were up-regulated significantly in hCASMC treated by ox-LDL and/or in human atherosclerotic plaque. Further studies indicated PAPP-A was the target gene of miR-490-3p. The miR-490-3p mimic could inhibit the up-regulation of PAPP-A induced by ox-LDL in hCASMC, which resulted in the suppression of the metalloprotease effect of PAPP-A on IGF-binding protein-4 (IGFBP-4). All these effects led to the inhibition of the proliferation of hCASMC induced by ox-LDL. Ox-LDL could inhibit the expression of miR-490-3p and IGF1, whereas increase IGF2 expression. The inhibition of miR0-490-3p up-regulated its target gene PAPP-A and then increased the proteolysis of IGFBP-4. The increased expression of IGF2 and proteolysis of IGFBP-4 might activate pathways independent or dependent on IGF axis by autocrine and paracrine mechanisms and resulted in the VSMC proliferation. Our results could help us to understand the mechanisms of the pro-atherogenic effects of ox-LDL and the effects of PAPP-A on atherosclerosis development.

In this study, we evaluate the effect of HO-1 upregulation on blood pressure and cardiac function in the new model of infarct spontaneous hypertensive rats (ISHR). Male spontaneous hypertensive rats (SHR) at 13 weeks (n = 40) and age-matched male Wistar (WT) rats (n = 20) were divided into six groups: WT (sham + normal saline (NS)), WT (sham + Co(III) Protoporphyrin IX Chloride (CoPP)), SHR (myocardial infarction (MI) + NS), SHR (MI + CoPP), SHR (MI + CoPP + Tin Mesoporphyrin IX Dichloride (SnMP)), SHR (sham + NS); CoPP 4.5 mg/kg, SnMP 15 mg/kg, for six weeks, one/week, i.p., n = 10/group. At the sixth week, echocardiography (UCG) and hemodynamics were performed. Then, blood samples and heart tissue were collected. Copp treatment in the SHR (MI + CoPP) group lowered blood pressure, decreased infarcted area, restored cardiac function (left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), +dp/dt_max, (−dp/dt_max)/left ventricular systolic pressure (LVSP)), inhibited cardiac hypertrophy and ventricular enlargement (downregulating left ventricular end-systolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and heart weight/body weight (HW/BW)), lowered serum CRP, IL-6 and Glu levels and increased serum TB, NO and PGI2 levels. Western blot and immunohistochemistry showed that HO-1 expression was elevated in the SHR (MI + CoPP) group, while co-administration with SnMP suppressed the benefit functions mentioned above. In conclusion, HO-1 upregulation can lower blood pressure and improve post-infarct cardiac function in the ISHR model. These functions may be involved in the inhibition of inflammation and the ventricular remodeling process and in the amelioration of glucose metabolism and endothelial dysfunction.

Background: High dietary fat intake is a major risk factor for development of cardiovascular and metabolic dysfunction including obesity, cardiomyopathy and hypertension. Methods: The present study was designed to examine effect of high fat (HF) diet on cardio-vascular structure and function in spontaneously hypertensive rats (SHR), fed HF diet for 15 weeks, a phenotype designed to mimic metabolic syndrome. Results: Development of metabolic syndrome like phenotype was confirmed using parameters, including body weight, total cholesterol and blood pressure levels. High fat diet impaired vascular relaxation by acetylcholine and exacerbated cardiac dysfunction in SHRs as evidenced by lower left ventricular function, and higher coronary resistance (CR) as compared to controls (p < 0.05). The histological examination revealed significant myocardial and peri-vascular fibrosis in hearts from SHRs on HF diet. This cardiac dysfunction was associated with increased levels of inflammatory cytokines, COX-2, NOX-2, TxB2 expression and increase in superoxide (O₂ ^-) levels in SHR fed a HF diet (p < 0.05). HO-1 induction via cobalt-protoporphyrin (CoPP,3 mg/kg), in HF fed rats, not only improved cardiac performance parameters, but also prevented myocardial and perivascular fibrosis. These effects of CoPP were accompanied by enhanced levels of cardiac adiponectin levels, pAMPK, peNOS and iNOS expression; otherwise significantly attenuated (p < 0.05) in HF fed SHRs. Prevention of such beneficial effects of CoPP by the concurrent administration of the HO inhibitor stannic mesoporphyrin (SnMP) corroborates the role of HO system in mediating such effects. Conclusion: In conclusion, this novel study demonstrates that up-regulation of HO-1 improves cardiac and vascular dysfunction by blunting oxidative stress, COX-2 levels and increasing adiponectin levels in hypertensive rats on HF diet.

Myocardial dysfunction and coronary macro/microvascular alterations are the hallmarks of diabetic cardiomyopathy and are ascribed to increased oxidative stress and altered nitric oxide synthase (NOS) activity. We hypothesize that pretreatment by cobalt-protoporphyrin IX (CoPP) ameliorates both myocardial function and coronary circulation in streptozotocin(STZ)-induced diabetic rats. Isolated hearts from diabetic rats in Langendorff configuration displayed lower left ventricular (LV) function and higher coronary resistance (CR) compared to hearts from control animals. CoPP treatment of diabetic animals (0.3mg/100g body weight i.p., once a week for three weeks) significantly increased all the contractile/relaxation indexes (p<0.01), while decreasing CR (p<0.01). CoPP enhanced HO-1 protein levels and reduced oxidative/nitrosative stress in diabetic animals, as indicated by the significant (p<0.05) decrease in heart GSSG/GSHtotal, O2-, malondialdehyde (MDA), and 3-nitrotyrosine levels. CoPP increased adiponectin levels and phosphorylation of AKT and AMPK and reversed the eNOS/iNOS expression imbalance observed in the untreated diabetic heart. Furthermore, after CoPP treatment, a rise in malonylCoA as well as a decrease in acetylCoA was observed in diabetic hearts. In this experimental model of diabetic cardiomyopathy, CoPP treatment improved both cardiac function and coronary flow by blunting oxidative/nitrosative stress, restoring eNOS/ iNOS expression balance and increasing HO-1 levels, thereby favoring improvement in both endothelial function and insulin sensitivity.

Objective: To investigate the levels of sex hormones and androgen receptor (AR) in elderly male patients and to explore a possible correlation with obesity. Methods: The cross-sectional study included 314 Elderly males (age ≥ 65 year). Of these subjects, 104 were healthy (age range 65–92 year; mean 71.38 ± 5.154 year), 74 were obese (65–87 year; 71.32 ± 4.74 year), and 111 were overweight (65–85 year; 71.43 ± 5.03 year). The following parameters were measured: total testosterone (TT), free testosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), estradiol (E2), luteinizing hormone, follicle-stimulating hormone and AR. Results: (i) The levels of TT and SHBG in the obesity group were significantly lower than those in non-obese subjects. (ii) Body mass index (BMI) negatively correlated with TT and SHBG. (iii) Multiple regression analysis revealed that TT (β: −0.230; p = 0.045) and SHBG (β: −0.163; p = 0.02) were statistically correlated with BMI. Conclusion: Testosterone levels in the obese population were significantly lower than in the non-obese population and there is a significant association between testosterone levels and the extent of obesity.