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Background: Fibrotic remodeling is an essential aspect of heart failure. Human kallistatin (KS, mouse Serpina3c homologs) inhibits fibrosis after myocardial infarction (MI) but the specific underlying mechanism is unknown., Methods: A total of 40 heart failure patients (HFPs) were enrolled and their plasma KS was measured using ELISA. Serpina3c -/- and C57BL/6 mice were used to construct the MI model. TGF-β1 or a hypoxic condition was established to interfere with the functioning of cardiac fibroblasts (CFs). RNA-seq was performed to assess the effect of Serpina3c on the transcriptome., Findings: The levels of KS were used as a predictor of readmission among the HFPs. Serpina3c expression decreased in MI hearts and CFs. Serpina3c -/- led to the aggravation of MI fibrosis, and increased the proliferation of CFs. The overexpression of Serpina3c in CFs had the opposite effect. Glycolysis-related genes were significantly increased in Serpina3c -/- group by RNA-seq. Enolase (ENO1), which is a key enzyme in glycolysis, increased most significantly. Inhibition of ENO1 could antagonize the promotion of Serpina3c -/- on the proliferation of CFs. Co-IP was performed to verify the interaction between Serpina3c and Nr4a1. Serpina3c -/- inhibited the acetylation of Nr4a1 and increased the degradation of Nr4a1. Activation of Nr4a1 could negatively regulate the expression of ENO1 and inhibited the proliferation of Serpina3c -/- CFs in Serpina3c -/- MI mice., Interpretation: Serpina3c inhibits the transcriptional activation of ENO1 by regulating the acetylation of Nr4a1, thereby reducing the fibrosis after MI by inhibiting glycolysis. Serpina3c is a potential target for prevention and treatment of heart failure after MI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: The objective of this study was to noninvasively measure the volume of myocardial infarction in rats, using delayed enhancement magnetic resonance imaging (MRI) in a coronary occlusion/reperfusion model on a 7-T scanner., Methods: At 24 h after cardiac ischemia, contrast-enhanced MRI was performed. Two distinct experimental groups were compared: one was subjected to permanent ischemia (PL) and the other was subjected to 30 min of ischemia followed by 24 h of reperfusion (IR). The sizes of enhanced regions were compared to triphenyltetrazolium chloride (TTC)-stained sections of the excised rat heart. Cardiomyocyte apoptosis was analyzed by TUNEL methods, and neutrophils and macrophages were quantitated after histology and immunohistochemical staining., Results: Twenty-four hours after ischemia, delayed hyperenhancement imaging was clearly visualized in the anterior left ventricular walls corresponding to the infarcted myocardium. In the PL group, infarct size was 37.2±9.8% (LV %) as measured by MRI and 38.8±9% (LV %) by TTC (P=NS). In the IR group, infarct size was 23.2±8.8% (LV %) as measured by MRI and 24.4±9.2% (LV %) by TTC (P=NS). Infarction volume measured with MRI was strongly correlated to TTC staining (R=0.82 for PL, R=0.973 for IR). Increased inflammatory cell infiltration was detected in the infarct area of the heart after reperfusion compared to permanent ligation (P<.01). The ratio of TUNEL-positive cardiomyocytes to total number of cardiomyocytes in the IR group was significantly reduced as compared to the PL group (P<.01)., Conclusions: MRI can accurately assess infarct size in intact rats early after MI. After transient arterial occlusion, the size of the myocardial infarct was found to be significantly smaller as compared to permanent occlusion., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To observe the effect of intracoronary transfer of autologous HO-1 overexpressed MSCs in porcine model of myocardial ischemia (1 h)/reperfusion., Methods: Apoptosis was assayed and cytokine concentrations in supernatant were measured in cells exposed to hypoxia-reoxygen in vitro. In vivo, Chinese male mini-pigs were allocated to the following treatment groups: control group (saline), MSCs group (MSCs), MSCs transfected with pcDNA3.1-nHO-1 (HO-1-MSCs). 1 x 10(7) of autologous stem cells or identical volume of saline was injected intracoronary into porcine hearts 1 h after ischemia. MRI assay and postmortem analysis were assessed 3 months after stem cell transplantation., Results: In vitro, cell apoptosis rate post hypoxia-reoxygen was significantly reduced in HO-1-MSCs group (30.30% +/- 7.64%) compared with that in MSCs group (56.93% +/- 4.68%, P < 0.001) and LacZ-MSCs group (55.88% +/- 4.38%, P < 0.001), VEGF was also significantly upregulated in HO-1-MSCs group [(768.44 +/- 78.38) pg/ml] compared with that in MSCs group [(555.27 +/- 67.67) pg/ml, P < 0.001] and LacZ-MSCs group [(522.97 +/- 71.45) pg/ml, P < 0.001]. In vivo, cardiac function was significantly improved in both MSCs transplantation groups compared to saline group (all P < 0.05 vs.saline) and the left ventricular ejection fraction was significantly higher in HO-1-MSCs group compared with that in MSCs group at 3 months after transplantation (53.50% +/- 2.09% vs. 49.54% +/- 2.74%, P = 0.017), capillary density in the peri-infarct area was also significantly higher in HO-1-MSC group than that in MSCs group [(14.59 +/- 2.39)/HPF vs. (11.78 +/- 2.48)/HPF, P = 0.033]., Conclusions: Efficacy of HO-1 overexpressed MSCs on improving cardiac function and promoting angiogenesis was greater than those by MSCs in this porcine ischemia/reperfusion model.

Background: Tissue kallikrein is a serine proteinase that generates the vasoactive kinin peptide, which produces vasodilatory, angiogenic, and antiapoptotic effects. In this study, we investigated the effect of a stable supply of kallikrein and kinin on ventricular remodeling and blood vessel growth in rats after myocardial infarction., Methods and Results: At 1 week after coronary artery ligation, tissue kallikrein or kinin was infused through a minipump for 4 weeks. At 5 weeks after myocardial infarction, kallikrein and kinin infusion significantly improved cardiac contractility and reduced diastolic dysfunction without affecting systolic blood pressure. Kallikrein and kinin infusion significantly increased capillary density in the noninfarcted region. Kallikrein and kinin infusion also reduced heart weight/body weight ratio, cardiomyocyte size, and atrial natriuretic peptide and brain natriuretic peptide expression in the noninfarcted area. Moreover, kallikrein and kinin infusion inhibited interstitial collagen deposition, collagen fraction volume, and collagen I and collagen III mRNA levels, transforming growth factor (TGF)-beta1 and plasminogen activator inhibitor-1 expression, and Smad2 phosphorylation. The effects of kallikrein and kinin on cardiac remodeling were associated with increased nitric oxide levels and reduced NADPH oxidase expression and activity, superoxide formation, and malondialdehyde levels. Furthermore, in cultured cardiac fibroblasts, kinin inhibited angiotensin II-stimulated TGF-beta1 production, and the effect was blocked by icatibant., Conclusion: These results indicate that a subdepressor dose of kallikrein or kinin can restore impaired cardiac function in rats with postinfarction heart failure by inhibiting hypertrophy and fibrosis and promoting angiogenesis through increased nitric oxide formation and suppression of oxidative stress and TGF-beta1 expression.

We investigated the effect of tissue kallikrein infusion on cardiac protection at acute and sub-acute phases after myocardial infarction (MI). Immediately after MI, rats were infused with purified tissue kallikrein, with or without icatibant (a kinin B2 receptor antagonist). Intramyocardial injection of kallikrein reduced myocardial infarct size and inhibited cardiomyocyte apoptosis at 1 day after MI associated with increased nitric oxide levels, Akt and glycogen synthase kinase-3beta phosphorylation and decreased caspase-3 activation. Kallikrein infusion for 7 days improved cardiac function, normalized left ventricular wall thickness and decreased monocyte/macrophage infiltration in the infarct heart. Kallikrein treatment reduced NADH oxidase expression and activity, superoxide formation and malondialdehyde levels, and reduced MAPK and Ikappa-Balpha phosphorylation, NF-kappaB activation and MCP-1 and VCAM-1 expression. Kallikrein's effects were all blocked by icatibant. These results indicate that kallikrein through kinin B2 receptor activation prevents apoptosis, inflammation and ventricular remodeling by increased nitric oxide formation and suppression of oxidative stress-mediated signaling pathways.