Phosphorylcholine antibodies restrict infarct size and left ventricular remodelling by attenuating the unreperfused post-ischaemic inflammatory response

Phosphorylcholine is a pro-inflammatory epitope exposed on apoptotic cells, and phosphorylcholine monoclonal immunoglobulin (Ig)G antibodies (PC-mAb) have anti-inflammatory properties. In this study, we hypothesize that PC-mAb treatment reduces adverse cardiac remodelling and infarct size (IS) following unreperfused transmural myocardial infarction (MI). Unreperfused MI was induced by permanent ligation of the left anterior descending (LAD) coronary artery in hypercholesterolaemic APOE*3-Leiden mice. Three weeks following MI, cardiac magnetic resonance (CMR) imaging showed a reduced LV end-diastolic volume (EDV) by 21% and IS by 31% upon PC-mAb treatment as compared to the vehicle control group. In addition, the LV fibrous content was decreased by 27% and LV wall thickness was better preserved by 47% as determined by histological analysis. Two days following MI, CCL2 concentrations, assessed by use of ELISA, were decreased by 81% and circulating monocytes by 64% as assessed by use of FACS analysis. Additionally, local leucocyte infiltration determined by immunohistological analysis showed a 62% decrease after three weeks. In conclusion, the local and systemic inflammatory responses are limited by PC-mAb treatment resulting in restricted adverse cardiac remodelling and IS following unreperfused MI. This indicates that PC-mAb holds promise as a therapeutic agent following MI limiting adverse cardiac remodelling.     

Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice

Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-1(-/-) mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-1(-/-) mice demonstrated that LV end-diastolic volume [52 +/- 4 (WT) vs. 71 +/- 6 (TIMP-1(-/-)) microl] and LV end-diastolic pressure [9.0 +/- 1.2 (WT) vs. 12.7 +/- 1.4 (TIMP-1(-/-)) mmHg] were significantly increased in the TIMP-1(-/-) mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-1(-/-) groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1(-/-) mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1(-/-) controls may have been an important contributory factor for the observed LV alterations in the TIMP-1(-/-) mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1.     

Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors

Effects of cardiac specific overexpression of beta(2)-adrenergic receptors (beta(2)-AR) on the development of heart failure (HF) were studied in wild-type (WT) and transgenic (TG) mice following myocardial infarction (MI) by coronary artery occlusion. Animals were studied by echocardiography at weeks 7 to 8 and by catheterization at week 9 after surgery. Post-infarct mortality, due to HF or cardiac rupture, was not different among WT mice, and there was no difference in infarct size (IS). Compared with the sham-operated group (all P < 0.01), WT mice with moderate (<36%) and large (>36%) IS developed lung congestion, cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV end-diastolic pressure (LVEDP), and suppressed maximal rate of increase of LV pressure (LV dP/dt(max)) and fractional shortening (FS). Whereas changes in organ weights and echo parameters were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate (dP/dt(max) 4,862 +/- 133 vs. 3,694 +/- 191 mmHg/s) and large IS groups (dP/dt(max) 4,556 +/- 252 vs. 3,145 +/- 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%, P < 0.05) and LVEDP levels (6 +/- 0.3 vs. 9 +/- 0.8 mmHg, P < 0.05) were also lower in TG than in WT mice with large IS. Thus beta(2)-AR overexpression preserved LV contractility following MI without adverse consequence.     

Inhibition of cardiac leptin expression after infarction reduces subsequent dysfunction

Leptin is known to exert cardiodepressive effects and to induce left ventricular (LV) remodelling. Nevertheless, the autocrine and/or paracrine activities of this adipokine in the context of post‐infarct dysfunction and remodelling have not yet been elucidated. Therefore, we have investigated the evolution of myocardial leptin expression following myocardial infarction (MI) and evaluated the consequences of specific cardiac leptin inhibition on subsequent LV dysfunction. Anaesthetized rats were subjected to temporary coronary occlusion. An antisense oligodesoxynucleotide (AS ODN) directed against leptin mRNA was injected intramyocardially along the border of the infarct 5 days after surgery. Cardiac morphometry and function were monitored by echocardiography over 11 weeks following MI. Production of myocardial leptin and pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐6 were assessed by ELISA. Our results show that (1) cardiac leptin level peaks 7 days after reperfused MI; (2) intramyocardial injection of leptin‐AS ODN reduces early IL‐1β and IL‐6 overexpression and markedly protects contractile function. In conclusion, our findings demonstrate that cardiac leptin expression after MI could contribute to the evolution towards heart failure through autocrine and/or paracrine actions. The detrimental effect of leptin could be mediated by pro‐inflammatory cytokines such as IL‐1β and IL‐6. Our data could constitute the basis of new therapeutic approaches aimed to improve post‐MI outcome.     

Relationship among LRP1 expression,Pyk2 phosphorylation and MMP‐9 activation in left ventricular remodelling after myocardial infarction

Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metalloproteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the activation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore the potential association between the low‐density lipoprotein receptor‐related protein 1 (LRP1) and MMP‐9 and MMP‐2 spatiotemporal expression after MI. Real‐time PCR and Western blot analyses showed that LRP1 mRNA and protein expression levels, respectively, were significantly increased in peri‐infarct and infarct zones at 10 and 21 days after MI. Confocal microscopy demonstrated high colocalization between LRP1 and the fibroblast marker vimentin, indicating that LRP1 is mostly expressed by cardiac fibroblasts in peri‐infarct and infarct areas. LRP1 also colocalized with proline‐rich tyrosine kinase 2 (pPyk2) and MMP‐9 in cardiac fibroblasts in ischaemic areas at 10 and 21 days after MI. Cell culture experiments revealed that hypoxia increases LRP1, pPyk2 protein levels and MMP‐9 activity in fibroblasts, without significant changes in MMP‐2 activity. MMP‐9 activation by hypoxia requires LRP1 and Pyk2 phosphorylation in fibroblasts. Collectively, our in vivo and in vitro data support a major role of cardiac fibroblast LRP1 levels on MMP‐9 up‐regulation associated with ventricular remodelling after MI.     

CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction

Post-myocardial infarction (MI), chemokine homing of inflammatory cells into the injured left ventricle (LV) regulates ventricular remodeling, in part by stimulating the extracellular matrix response. The CC chemokine receptor 5 (CCR5) is a key chemokine receptor expressed on macrophages, and CCR5 ligands are highly upregulated post-MI. We hypothesized that deletion of CCR5 would attenuate adverse remodeling by decreasing inflammatory cell recruitment. Accordingly, we examined LV function, macrophage recruitment and activation, and collagen content in wild-type (WT, n = 25) and CCR5 null (n = 33) mice at 7 days post-MI. Both groups had similar infarct sizes (44 ± 2% in WT and 42 ± 2% in CCR5 null; P = 0.37). However, the LV remodeling index (end diastolic volume/LV mass) increased to a larger extent in CCR5 null (1.28 ± 0.08 μl/mg for CCR5 null and 1.02 ± 0.06 μl/mg for WT; P < 0.05). Although numbers of infiltrated macrophages were similar in WT and CCR5 null mice, CCR5-deficient macrophages isolated from the infarct zone displayed >50% decrease in gene expression levels of proinflammatory activation markers (interleukin-1β, interleukin-6, and tumor necrosis factor-α), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-β1) compared with WT (all P < 0.05). Concomitant with the reduced macrophage activation, heat shock protein-47 and collagen type I precursor levels in the infarct region decreased in the CCR5 null (1.2 ± 0.3 units in the CCR5 null and 2.3 ± 0.4 units in the WT; P < 0.05), while collagen fragments increased (88.3 ± 5.9 units in the CCR5 null and 32.7 ± 8.5 units in the WT; P < 0.05). We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates an imbalance in collagen metabolism and increases the remodeling index.     

Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction

Matrix metalloproteinase-2 (MMP-2) is prominently overexpressed both after myocardial infarction (MI) and in heart failure. However, its pathophysiological significance in these conditions is still unclear. We thus examined the effects of targeted deletion of MMP-2 on post-MI left ventricular (LV) remodeling and failure. Anterior MI was produced in 10- to 12-wk-old male MMP-2 knockout (KO) and sibling wild-type (WT) mice by ligating the left coronary artery. By day 28, MI resulted in a significant increase in mortality in association with LV cavity dilatation and dysfunction. The MMP-2 KO mice had a significantly better survival rate than WT mice (56% vs. 85%, P < 0.05), despite a comparable infarct size (50 +/- 3% vs. 51 +/- 3%, P = not significant), heart rate, and arterial blood pressure. The KO mice had a significantly lower incidence of LV rupture (10% vs. 39%, P < 0.05), which occurred within 7 days of MI. The KO mice exerted less LV cavity dilatation and improved fractional shortening after MI by echocardiography. The LV zymographic MMP-2 level significantly increased in WT mice after coronary artery ligation; however, this was completely prevented in KO mice. In contrast, the increase in the LV zymographic MMP-9 level after MI was similar between KO and WT mice. MMP-2 activation is therefore considered to contribute to an early cardiac rupture as well as late LV remodeling after MI. The inhibition of MMP-2 activation may therefore be a potentially useful therapeutic strategy to manage post-MI hearts.     

Gender-specific patterns of left ventricular and myocyte remodeling following myocardial infarction in mice deficient in the angiotensin II type 1a receptor

Left ventricular (LV) remodeling after myocardial infarction (MI) results from hypertrophy of myocytes and activation of fibroblasts induced, in part, by ligand stimulation of the ANG II type 1 receptor (AT1R). The purpose of the present study was to explore the specific role for activation of the AT 1a R subtype in post-MI remodeling and whether gender differences exist in the patterns of remodeling in wild-type and AT 1a R knockout (KO) mice. AT 1a R-KO mice and wild-type littermates underwent coronary ligation to induce MI or sham procedures; echocardiography and hemodynamic evaluation were performed 6 wk later, and LV tissue was harvested for infarct size determination, morphometric measurements, and gene expression analysis. Survival and infarct size were similar among all male and female wild-type and AT 1a R-KO mice. Hemodynamic indexes were also similar except for lower systolic blood pressure in the AT 1a R-KO mice compared with wild-type mice. Male and female wild-type and male AT 1a R-KO mice developed similar increases in LV chamber size, LV mass corrected for body weight (LV/BW), and myocyte cross-sectional area (CSA). However, female AT 1a R-KO mice demonstrated no increase in LV/BW and myocyte CSA post-MI compared with shams. Both male and female wild-type mice demonstrated higher atrial natriuretic peptide (ANP) levels after MI, with female wild types being significantly greater than males. However, male and female AT 1a R-KO mice developed no increase in ANP gene expression with MI despite an increase in LV mass and myocyte size in males. These data support that gender-specific patterns of LV and myocyte hypertrophy exist after MI in mice with a disrupted AT 1a R gene, and suggest that myocyte hypertrophy post-MI in females relies, in part, on activation of the AT 1a R. Further work is necessary to explore the potential mechanisms underlying these gender-based differences.     

Zinc Finger Protein ZBTB20 protects against cardiac remodelling post‐myocardial infarction via ROS‐TNFα/ASK1/JNK pathway regulation

This study aims to determine the efficacy of Zinc finger protein ZBTB20 in treatment of post‐infarction cardiac remodelling. For this purpose, left anterior descending (LAD) ligation was operated on mice to induce myocardial infarction (MI) with sham control group as contrast and adeno‐associated virus (AAV9) system was used to deliver ZBTB20 to mouse heart by myocardial injection with vehicle‐injected control group as contrast two weeks before MI surgery. Then four weeks after MI, vehicle‐treated mice with left ventricular (LV) remodelling underwent deterioration of cardiac function, with symptoms of hypertrophy, interstitial fibrosis, inflammation and apoptosis. The vehicle‐injected mice also showed increase of infarct size and decrease of survival rate. Meanwhile, the ZBTB20‐overexpressed mice displayed improvement after MI. Moreover, the anti‐apoptosis effect of ZBTB20 was further confirmed in H9c2 cells subjected to hypoxia in vitro. Further study suggested that ZBTB20 exerts cardioprotection by inhibiting tumour necrosis factor α/apoptosis signal‐regulating kinase 1 (ASK1)/c‐Jun N‐terminal kinase 1/2 (JNK1/2) signalling, which was confirmed by shRNA‐JNK adenoviruses transfection or a JNK activator in vitro as well as ASK1 overexpression in vivo. In summary, our data suggest that ZBTB20 could alleviate cardiac remodelling post‐MI. Thus, administration of ZBTB20 can be considered as a promising treatment strategy for heart failure post‐MI.Significance Statement: ZBTB20 could alleviate cardiac remodelling post‐MI via inhibition of ASK1/JNK1/2 signalling.     

Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition

Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-MI remodeling in mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 (30 mg.kg(-1).day(-1)) on LV geometry and function (conductance volumetry) after MI in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into four groups: WT-MI/MMPi (n = 10), TIMP1-KO-MI/MMPi (n = 10), WT-MI (n = 22), and TIMP1-KO-MI (n = 23). LV end-diastolic volume (EDV) and ejection fraction were determined 14 days after MI. Age-matched WT (n = 20) and TIMP1-KO (n = 28) mice served as reference controls. LVEDV was similar under control conditions in WT and TIMP1-KO mice (36 +/- 2 and 40 +/- 2 microl, respectively) but was greater in TIMP1-KO-MI than in WT-MI mice (48 +/- 2 vs. 61 +/- 5 microl, P < 0.05). LVEDV was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 +/- 2 and 36 +/- 2 microl, respectively, P < 0.05) but was reduced to the greatest degree in TIMP1-KO mice (P < 0.05). LV ejection fraction was reduced in both groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. These unique results demonstrated that myocardial TIMP-1 plays a regulatory role in post-MI remodeling and that the accelerated myocardial remodeling induced by TIMP-1 gene deletion can be pharmacologically "rescued" by MMP inhibition. These results define the importance of local endogenous control of MMP activity with respect to regulating LV structure and function after MI.     

Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

Aims

Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI.

Methods and Results

Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15.

Conclusion

Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.     

Danqi soft capsule prevents infarct border zone remodelling and reduces susceptibility to ventricular arrhythmias in post‐myocardial infarction rats

Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post‐myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post‐MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post‐MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α‐smooth muscle actin (α‐SMA), transforming growth factor‐β1 (TGF‐β1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF‐β1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post‐MI period.     

Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure

The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD(-/-) mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation. After 2 days, myocardial infarct size was smaller and left ventricular (LV) function was better preserved in CypD(-/-) mice compared to WT mice. After 28 days, when compared to WT mice, in the CypD(-/-) mice, mortality was halved, myocardial infarct size was reduced, LV systolic function was better preserved, LV dilatation was attenuated and in the remote non-infarcted myocardium, there was less cardiomyocyte hypertrophy and interstitial fibrosis. Finally, ex vivo fibroblast proliferation was found to be reduced in CypD(-/-) cardiac fibroblasts, and in WT cardiac fibroblasts treated with the known CypD inhibitors, cyclosporin-A and sanglifehrin-A. Following an MI, mice lacking CypD have less mortality, smaller infarct size, better preserved LV systolic function and undergo less adverse LV remodelling. These findings suggest that the inhibition of mitochondrial CypD may be a novel therapeutic treatment strategy for post-MI heart failure.     

Age-related differences in postinfarct left ventricular rupture and remodeling

Cardiac rupture is more prevalent in elderly patients with first onset of acute myocardial infarct (MI), but the mechanism remains unexplored. We investigated the differences in the incidence of cardiac rupture and early left ventricular (LV) remodeling following coronary artery ligation between old (12-mo) and young (3-mo) C57Bl/6 male mice and explored responsible mechanisms. The incidence of rupture within 1 wk after MI was significantly higher in old than in young mice (40.7 vs. 18.3%, P = 0.013) despite a similar infarct size in both age groups. Old mice dying of rupture had more severe infarct expansion than young counterparts. Echocardiography and catheterization at day 7 revealed more profound LV chamber dilatation and dysfunction as well as higher blood pressures in aged mice. At day 3 after MI immediately before the peak of rupture occurrence, we observed significantly higher content of type I and III collagen, a greater density of macrophage and neutrophil, and markedly enhanced mRNA expression of inflammatory cytokines in the infarcted myocardium in old than in young mice. Furthermore, a more dramatic increment of matrix metalloproteinase (MMP)-9 activity was found in old than in young infarcted hearts, in keeping with enhanced inflammatory response. Collectively, these results revealed that old mice had a higher risk of post-MI cardiac rupture despite a higher level of collagen content and cross-linking. Enhanced inflammatory response and subsequent increase in MMP-9 activity together with higher blood pressure are important factors responsible for the higher risk of cardiac rupture and more severe LV remodeling in the aged heart following acute MI.     

Cardiac-specific overexpression of diacylglycerol kinase zeta attenuates left ventricular remodeling and improves survival after myocardial infarction

Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, G(q) protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported that DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. The purpose of this study was to examine whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. LV chamber dilatation (4.12 +/- 0.10 vs. 4.53 +/- 0.32 mm, P < 0.01), reduction of LV systolic function (34.8 +/- 8.3% vs. 28.3 +/- 4.8%, P < 0.01), and increases in LV weight (95 +/- 3.6 vs. 111 +/- 4.1 mg, P < 0.05) and lung weight (160 +/- 15 vs. 221 +/- 25 mg, P < 0.05) at 4 wk after MI were attenuated in DGKzeta-TG mice compared with WT mice. In the noninfarct area, fibrosis fraction (0.51 +/- 0.04, P < 0.01) and upregulation of profibrotic genes, such as transforming growth factor-beta1 (P < 0.01), collagen type I (P < 0.05), and collagen type III (P < 0.01), were blocked in DGKzeta-TG mice. The survival rate at 4 wk after MI was higher in DGKzeta-TG mice than in WT mice (61% vs. 37%, P < 0.01). In conclusion, these results demonstrate the first evidence that DGKzeta suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKzeta may be a potential novel therapeutic target to prevent LV remodeling after MI.     

Interleukin‐38 alleviates cardiac remodelling after myocardial infarction

Excessive immune‐mediated inflammatory reaction plays a deleterious role in ventricular remodelling after myocardial infarction (MI). Interleukin (IL)‐38 is a newly characterized cytokine of the IL‐1 family and has been reported to exert a protective effect in some autoimmune diseases. However, its role in cardiac remodelling post‐MI remains unknown. In this study, we found that the expression of IL‐38 was increased in infarcted heart after MI induced in C57BL/6 mice by permanent ligation of the left anterior descending artery. In addition, our data showed that ventricular remodelling after MI was significantly ameliorated after recombinant IL‐38 injection in mice. This amelioration was demonstrated by better cardiac function, restricted inflammatory response, attenuated myocardial injury and decreased myocardial fibrosis. Our results in vitro revealed that IL‐38 affects the phenotype of dendritic cells (DCs) and IL‐38 plus troponin I (TNI)‐treated tolerogenic DCs dampened adaptive immune response when co‐cultured with CD4⁺T cells. In conclusion, IL‐38 plays a protective effect in ventricular remodelling post‐MI, one possibility by influencing DCs to attenuate inflammatory response. Therefore, targeting IL‐38 may hold a new therapeutic potential in treating MI.     

The effect of hydrogel injection on cardiac function and myocardial mechanics in a computational post-infarction model

An emerging therapy to limit adverse heart remodelling following myocardial infarction (MI) is the injection of polymers into the infarcted left ventricle (LV). In the few numerical studies carried out in this field, the definition and distribution of the hydrogel in the infarcted myocardium were simplified. In this computational study, a more realistic biomaterial distribution was simulated after which the effect on cardiac function and mechanics was studied. A validated finite element heart model was used in which an antero-apical infarct was defined. Four infarct models were created representing different temporal phases in the progression of a MI. Hydrogel layers were simulated in the infarcted myocardium in each model. Biomechanical and functional improvement of the LV was found after hydrogel inclusion in the ischaemic models representing the early phases of MI. In contrast, only functional but no mechanical restitution was shown in the scar model due to hydrogel presence.     

Protective role of 5‐azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis

We examined whether a shift in macrophage phenotype could be therapeutic for myocardial infarction (MI). The mouse macrophage cell line RAW264.7 was stimulated with peptidoglycan (PGN), with or without 5-azacytidine (5AZ) treatment. MI was induced by ligation of the left anterior descending coronary artery in rats, and the rats were divided into two groups; a saline-injection group and a 5AZ-injection group (2.5 mg/kg/day, intraperitoneal injection). LV function was evaluated and immunohistochemical analyses were performed 2 weeks after MI. Cardiac fibrosis was induced by angiotensin II (AngII) infusion with or without 5AZ (5 mg/kg/day) in mice. Nitric oxide was produced by PGN, which was reduced by 77.87% after 5AZ treatment. Both induction of inducible nitric oxide synthase (iNOS) and iNOS promoter activity by PGN were inhibited by 5AZ. Ejection fraction (59.00 ± 8.03% versus 42.52 ± 2.58%), contractility (LV dP/dt-max, 8299.76 ± 411.56 mmHg versus 6610.36 ± 282.37 mmHg) and relaxation indices (LV dP/dt-min, −4661.37 ± 210.73 mmHg versus −4219.50 ± 162.98 mmHg) were improved after 5AZ administration. Cardiac fibrosis in the MI+5AZ was 8.14 ± 1.00%, compared with 14.93 ± 2.98% in the MI group (P < 0.05). Arginase-1(+)CD68(+) macrophages with anti-inflammatory phenotype were predominant in the infarct border zone of the MI+5AZ group, in comparison with the MI group. AngII-induced cardiac fibrosis was also attenuated after 5AZ administration. In cardiac fibroblasts, pro-fibrotic mediators and cell proliferation were increased by AngII, and these increases were attenuated after 5AZ treatment. 5AZ exerts its cardiac protective role through modulation of macrophages and cardiac fibroblasts.     

Does coronary vasodilation after adenosine override endothelin-1-induced coronary vasoconstriction?

In vivo evaluation of the transmural extension of myocardial infarction (TEI) is crucial to prediction of viability and prognosis. With the rise of transgenic technology, murine myocardial infarction (MI) models are increasingly used. Our study aimed to evaluate systolic strain rate (SR), a new parameter of regional function, to quantify TEI in a murine model of acute MI induced by various durations of ischemia followed by 24 h of reperfusion. Global and regional left ventricular (LV) function were assessed by echocardiography (13 MHz, Vivid 7, GE) in 4 groups of wild-type mice (C57BL/6, 2 mo old): a sham-treated group (n = 10) and three MI groups [30 (n = 11), 60 (n = 10), and 90 (n = 9) min of left coronary artery occlusion]. Conventional LV dimensions, anterior wall (AW) thickening, and peak systolic SR were measured before and 24 h after reperfusion. Area at risk (AR) was measured by blue dye and infarct size (area of necrosis, AN) and TEI by triphenyltetrazolium chloride staining. AN increased with ischemia duration (25 +/- 2%, 56 +/- 5%, 71 +/- 6% of AR for 30, 60, and 90 min, respectively; P < 0.05). LV end-diastolic volume significantly increased with ischemia duration (30 +/- 5, 34 +/- 5, 43 +/- 5 microl; P < 0.05), whereas LV ejection fraction decreased (63 +/- 5%, 58 +/- 6%, 46 +/- 5%; P < 0.05). AW thickening decrease was not influenced by ischemia duration. Conversely, systolic SR decreased with ischemia duration (13 +/- 5, 4 +/- 3, -2 +/- 6 s(-1); P < 0.05) and was significantly correlated with TEI (r = 0.89, P < 0.01). Receiver operating characteristic (ROC) curves identified systolic SR as the most accurate parameter to predict TEI. In conclusion, in a murine model of MI, SR imaging is superior to conventional echocardiography to predict TEI early after MI.     

Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells

To investigate the prevention of cardiac remodelling and inflammatory immune response after myocardial infarction (MI) via ACEI regulating dendritic cells (DCs), we explored whether the protective effect of ACEI was repressed under hyperlipidemic environment. In vivo, the survival rate and left ventricular function of the mice were recorded on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were assessed for Ang II concentration, inflammatory cytokines and DCs expression. In vitro, DCs were treated with ox-LDL + Ang II, simulating the internal environment of MI in ApoE^−/− mice to explore the mechanism involved in the DCs maturation and inflammation. Under hyperlipidemic circumstances, we found that the cardioprotective effect of ACEI was attenuated through regulating DCs maturation and inflammation after MI, affecting survival rate and left ventricular function. Effects of lisinopril on the release of spleen-derived DCs and myocardial infiltration were also reduced under hyperlipidemic conditions. In vitro, immune maturation and inflammation of DCs were further induced by ox-LDL on the basis of Ang II treatment, as indicated by the upregulation of CD83, CD86, and the expressions of cytokines and chemokines. Furthermore, ox-LDL could activate TLR4-MyD88 signalling pathway, promoting IRAK-4 and NF-κB. The present study demonstrated that ACEI reduced the recruitment of DCs to the infarct site, leading to a higher survival rate and improved function. However, this effect was inhibited under hyperlipidemic environment. TLR4-MyD88 signalling pathway may be responsible for the molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox-LDL.