Abstract 368: Biomechanical Properties of Scar ECM: from the Acute to Chronic Stages of Myocardial Infarction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Bryn Brazile ◽  
J. R Butler ◽  
Sourav Patnaik ◽  
Yanyi Xu ◽  
Andrew Claude ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Function ◽  
Sodium Dodecyl ◽  
Longitudinal Direction ◽  
Biomechanical Properties ◽  
Circumferential Direction ◽  
Heart Cell ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Biaxial Behavior

Introduction: Myocardial infarction (MI) affects more than 8 million Americans, causing massive heart cell death and heart function decrease. To better understand the scar biomechanics, we characterized the mechanical properties of pure scar ECM, obtained by decellularizing the MI tissues. Materials and Methods: Infarcted rat hearts were generated by a permanent left coronary artery ligation (PLCAL) and harvested at 15 min, 1, 2, and 4 weeks (per acute to chronic stages of MI)(N = 6 each). Scar ECM were obtained by decellularizing the infarcted hearts in 0.1% sodium dodecyl sulfate (SDS) solution for 3 weeks. Scar ECM specimens were trimmed into square shape, and then subjected to biaxial testing with one edge aligned with the circumferential direction and the other edge aligned with the longitudinal direction of the rat heart. After 10 cycle preconditioning, an equibiaxial tension protocol of T circ : T rad = 30:30 N/m was performed to capture the tissue biaxial behavior. Results and Discussion: Scar ECM 15 minutes through 4 weeks post infarction showed a stiffening biaxial behavior along with the time (Fig.1). The decrease of extensibility along longitudinal direction was more noticeable than circumferential direction, which led to a decrease in degree of anisotropy. Conclusions: Scar ECM biomechanics showed a stiffening behavior with a marked reduction in extensibility (longitudinal) with time. This change in biomechanical properties can be correlated to the collagen structure changes with progression of MI. Knowledge of the structural-mechanical relationship of scar ECM will help us understand MI progression and help formulate regenerative therapies.

Abstract 249: Chronic Neuregulin-1β Treatment Mitigates the Progression of Post-myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Manisha Gupte ◽  
Hind Lal ◽  
Firdos Ahmad ◽  
Lin Zhong ◽  
Douglas B Sawyer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 1 Diabetes ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Aim: Neuregulin-1β (NRG-1β), a growth factor critical for cardiac development as well as maintenance of heart function after injury has been shown to significantly improve heart function in preclinical rodent models. Importantly, number of studies are ongoing to test the efficacy of NRG-1β as a treatment for patients with chronic heart failure. However, the efficacy of recombinant NRG-1β in a typ1 diabetic model of heart failure due to myocardial infarction (MI) has not been investigated. The aim of the present study was to determine the efficacy of exogenous NRG-1β to improve residual cardiac function after MI in type1 diabetic rats. Methods and Results: Sprague Dawley rats were induced type 1 diabetes by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 diabetes, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 ug/kg) twice a week for 7 weeks, starting two weeks prior to experimental MI. Residual left ventricular (LV) function was significantly greater in the NRG-1β-treated STZ-diabetic MI group compared to the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. Furthermore, NRG-1β treatment in STZ-diabetic MI rats reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes. Conclusion: This study demonstrates that augmentation of NRG-1β signaling in STZ-diabetic post-MI rats via therapy with exogenous recombinant NRG-1β will alleviate subsequent HF through improvements in residual LV function via protection against adverse remodeling and apoptosis.

Abstract 116: Myelopoiesis Following Myocardial Ischemia (MI) Involves Activation of the Nlrp3 Inflammasome by Neutrophil-derived S100a8/a9

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Prabhakara R Nagareddy ◽  
Rahul Annabathula ◽  
Saojing Ye ◽  
Yuri Klyachkin ◽  
Ahmed Abdel-Latif ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Myocardial Damage ◽  
Heart Cell ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Hematopoietic Stem ◽  
Coronary Syndrome ◽  
Molecular Events

Ischemic myocardial damage triggers leukocytosis particularly the production of monocytes and neutrophils from the bone marrow and spleen (myelopoiesis). These cells infiltrate the evolving myocardial wound, degrade extracellular matrix and aid in the clearance of dead cardiac myocytes and their debris. Although this inflammatory process is a prerequisite for tissue healing, it is non-specific and often blunt. If unchecked, excessive production of monocytes and neutrophils may result in abnormal ventricular remodeling and heart failure. The myocardial cellular and molecular events that orchestrate with the BM/spleen to regulate myelopoiesis remain unclear. We report here that the number of circulating monocytes and neutrophils peak within 24 hours following coronary artery ligation (LAD) in mice. This is due to expansion and proliferation of hematopoietic stem and multi-potential progenitor cells (HSPC) in the BM as well as extra medullary hematopoiesis in the spleen. MI induced -myelopoiesis was associated with a dramatic increase in the expression of S100a8/a9 (a damage associated molecular pattern), its receptor (Tlr4), the Nlrp3 inflammasome and pro-IL1β in the heart. Cell separation studies revealed that the infiltrating neutrophils and cardiac fibroblasts are the predominant source of S100a8/a9 and the Nlrp3 inflammasome respectively in the heart. Further, deletion of s100a8/a9 not only reduced MI -induced myelopoiesis but also significantly improved the mortality and cardiac function in mice following LAD. These data supports our hypothesis that neutrophil-derived S100a8/a9 interact with Tlr4 on cardiac fibroblasts to induce the Nlrp3 inflammasome and produce IL1β, which in turn stimulates IL-1R on HSPCs to promote myelopoiesis. Pharmacological strategies aimed at inhibition of S100a8a/9 or the Nlrp3 inflammasome-mediated production of IL1β may be a promising approach to limit inflammation following acute coronary syndrome.

Abstract 177: Ticagrelor, but not Clopidogrel, Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yumei Ye ◽  
Jose R Perez-Polo ◽  
Manjyot K Nanhwan ◽  
Sven Nylander ◽  
Yochai Birnbaum
Keyword(s):  
Myocardial Infarction ◽  
Platelet Aggregation ◽  
Reperfusion Injury ◽  
Heart Function ◽  
Oral Treatment ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Ventricular Ejection Fraction

Background: Clopidogrel (C) and Ticagrelor (T) are P2Y12 ADP receptor antagonists. In addition, ticagrelor inhibits adenosine cell uptake. In PLATO trial T reduced the incidence of the primary composite endpoint myocardial infarction, stroke or cardiovascular death over C in patients with acute coronary syndromes. Previous data show that 7d pretreatment with T limits infarct size (IS) in rats. We compared the effects of C and T, administered just before reperfusion on IS. We also assessed the effect of T and C, administered just before reperfusion and/or 6w oral treatment on cardiac remodeling. Methods: Rats underwent 30min coronary artery ligation. 1) At 25min of ischemia rats received intraperitoneal (IP) vehicle, T (10 or 30mg/kg), or C (12.5mg/kg). Area at risk (AR) was assessed by blue dye and IS by TTC staining 24h after reperfusion. 2) Rats received vehicle without (sham) or with (control) coronary ischemia, T (30mg/kg) IP (TIP), T (300mg/kg/d) oral for 6w, started a day after reperfusion (TPO), TIP+PO (TIPPO), or C (12.5mg/kg IP +62.5mg/kg/d PO for 6w). LV dimensions and function was assessed by echo at 6w. Results: 1) AR was comparable among groups. IS was 45.3±1.7% of the AR in the control group. T10 (31.5±1.8%; p=0.001) and T30 (21.4±2.6% p<0.001) significantly reduced IS, whereas C (42.4±2.6%) had no effect. Platelet aggregation in the controls was 64.7±1.3% and was comparable in T30 (24.9±1.8%) and C (23.2±1.8%) at 2h post reperfusion. T30 increased Akt, eNOS and ER1/2 phosphorylation 4h after reperfusion, whereas C had no effect. 2) Platelet aggregation at 1w oral treatment was 59.7±3.2% in the control group and was comparable in TIPPO (18.1±1.3%) and C (17.4±0.7%). Left ventricular ejection fraction was 77.6±0.9%*, 44.8±3.5%, 69.5±1.6%*, 69.2±1.0%*, 76.3±1.2%*, and 37.4±3.7% in the sham, vehicle, TIP, TPO, TIPPO and C treated group, respectively (*p<0.001 vs. vehicle). Left ventricular diameters at diastole and systole showed the same pattern. Conclusions: T, but not C, administered just before reperfusion protects against reperfusion injury. Oral T (in combination or not with acute treatment just before reperfusion) treatment for 6w improves heart function. C, despite achieving similar degree of platelet inhibition had no effect on remodeling.

Cardiac adaptations to endurance training in rats with a chronic myocardial infarction

1989 ◽  
Vol 66 (2) ◽  
pp. 712-719 ◽  
Author(s):  
T. I. Musch ◽  
R. L. Moore ◽  
P. G. Smaldone ◽  
M. Riedy ◽  
R. Zelis
Keyword(s):  
Myocardial Infarction ◽  
Endurance Training ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Coronary Artery Ligation ◽  
Maximal Heart Rate ◽  
Chronic Myocardial Infarction ◽  
Artery Ligation ◽  
Training Paradigm ◽  
Myosin Isozyme

The hemodynamic response to maximal exercise was determined in sedentary and trained rats with a chronic myocardial infarction (MI) produced by coronary artery ligation and in rats that underwent sham operations (SHAM). Infarct size in the MI groups of rats comprised 28–29% of the total left ventricle and resulted in both metabolic and hemodynamic changes that suggested that these animals had moderate compensated heart failure. The training regimen used in the present study produced significant increases in maximal O2 uptake (VO2max) when expressed in absolute terms (ml/min) or when normalized for body weight (ml.min-1.kg-1) and consisted of treadmill running at work loads that were equivalent to 70–80% of the animal's VO2max for a period of 60 min/day, 5 days/wk over an 8- to 10-wk interval. This training paradigm produced two major cardiocirculatory adaptations in the MI rat that had not been elicited previously when using a training paradigm of a lower intensity. First, the decrement in the maximal heart rate response to exercise (known as “chronotropic incompetence”) found in the sedentary MI rat was completely reversed by endurance training. Second, the downregulation of cardiac myosin isozyme composition from the fast ATPase V1 isoform toward the slower ATPase (V2 and V3) isoforms in the MI rat was partially reversed by endurance training. These cardiac adaptations occurred without a significant increase in left ventricular pump function as an increase in maximal cardiac output (Qmax) and maximal stroke volume (SVmax) did not occur in the trained MI rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of Myocardial Infarction with Sequential Ligation of the Left Anterior Descending Artery and Its Diagonal Branch in Dogs and Sheep

2003 ◽  
Vol 26 (4) ◽  
pp. 351-357 ◽  
Author(s):  
W.G. Kim ◽  
Y.C. Shin ◽  
S.W. Hwang ◽  
C. Lee ◽  
C.Y. Na
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Pulmonary Artery ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Suitable Model ◽  
Artery Ligation ◽  
Diagonal Branch ◽  
Left Anterior Descending Artery ◽  
Arterial Blood

We report a comparison of the effects of myocardial infarction in dogs and sheep using sequential ligation of the left anterior descending artery (LAD) and its diagonal branch (DA), with hemodynamic, ultrasonographic and pathological evaluations. Five animals were used in each group. After surgical preparation, the LAD was ligated at a point approximately 40% of the distance from the apex to the base of the heart, and after one hour, the DA was ligated at the same level. Hemodynamic and ultrasonographic measurements were performed preligation, 30 minutes after LAD ligation, and 1 hour after DA ligation. As a control, two animals in each group were used for the simultaneous ligation of the LAD and the DA. Two months after the coronary ligation, the animals were evaluated as previously, and killed for postmortem examination of their hearts. All seven animals in the dog group survived the experimental procedures, while in the sheep group only animals with sequential ligation of the LAD and DA survived. Statistically significant decreases in systemic arterial blood pressure and cardiac output, and an increase in the pulmonary artery capillary wedge pressure (PACWP) were observed one hour after sequential ligation of the LAD and its DA in the sheep, while only systemic arterial pressures decreased in the dog. Ultrasonographic analyses demonstrated variable degrees of anteroseptal dyskinesia and akinesia in all sheep, but in no dogs. Data two months after coronary artery ligation showed significant increases in central venous pressure, pulmonary artery pressure, and PACWP in the sheep, but not in the dog. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension in ultrasonographic studies were also increased only in the sheep. Pathologically, the well-demarcated thin-walled transmural anteroseptal infarcts with chamber enlargement were clearly seen in all specimens of sheep, and only-mild-to-moderate chamber enlargements with endocardial fibrosis were observed in the dog hearts. In conclusion, this study confirms that the dog is not a suitable model for myocardial infarction with failure by coronary artery ligation despite negligent operative mortality, when compared directly with an ovine model.

Abstract 12648: Deletion of 12/15 Lipoxygenase Improves Left Ventricle Function and Survival by Resolving Inflammation Post Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vasundhara Kain ◽  
Kevin A Ingle ◽  
Janusz Kabarowski ◽  
Sumanth D Prabhu ◽  
Ganesh V Halade
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Survival Rates ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Lv Remodeling ◽  
Early Expression ◽  
Cox 2

12/15 lipoxygenase (LOX) is crucial in the inflammatory process leading to diabetes and atherosclerosis. However, the role of 12/15 LOX in myocardial infarction (MI) and left ventricle (LV) remodeling is unclear. We assessed the role of 12/15 LOX in resolving inflammation in post-MI LV remodeling. 8-12 weeks old C57BL/6J wild-type (WT; n=67) and 12/15 LOX (LOX –/– ; n=78) male mice were subjected to permanent coronary artery ligation surgery and monitored through day (d)1 and d5. No MI surgery mice were maintained as d0 naïve controls. LOX -/- mice showed higher survival rate, improved fractional shortening with reduced remodeling and edema index than WT at d1 and d5 post-MI (all p<0.05). LOX -/- mice showed increased Cxcl5 expression at d1 post-MI, consistent with stimulated neutrophil recruitment in the infarct region that was decreased at d5 compared to WT. LOX -/- mice infarct had increased expression of Ccl2 and Cxcl1, that stimulated an earlier recruitment of monocytes with increased macrophages population at d5 (all p<0.05) compared to WT. The altered kinetics of immune cells post-MI indicates a rapid resolving phase, through increase in alternative macrophage phenotypes with reduced collagen density in LOX -/- mice compared to WT mice at d5 post-MI. LOX -/- mice showed a coordinated COX-1 and COX-2 response at d1 post MI, leading to an evident increase in 5-LOX and hemoxygenase-1 (HO-1) at d5 post-MI. 12/15 LOX deletion enhanced the recruitment of alternative macrophages with secretion of HO-1 to resolve inflammation. In-vitro addition of LOX metabolite 12 hydroxyeicosatetraenoic acid to LOX -/- fibroblast induced early expression of COX-2 and 5-LOX compared to WT, indicating 5LOX role in resolution of inflammation. Post-MI increased expression of TIMP-1 and decrease in MMP-9 at d1 and α-SMA at d5 in LOX -/- mice suggested controlled differentiation of fibroblast-to-myofibroblast which is key event during ventricular tissue repair and resolving phase. This change is supported by increased expression of tgf-βi, ctgf and admats-2 (all P<0.05) at d5 post MI. In conclusion, absence of 12/15 LOX improves post-MI survival rates and attenuates LV dysfunction by resolving inflammation through coordination of 5-LOX and HO-1 as key inflammation resolving enzymes.

Abstract 48: Myelopoiesis Following Myocardial Ischemia (MI) Involves Activation of the Nlrp3 Inflammasome by Neutrophil-Derived S100a8/a9

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Prabhakara R Nagareddy ◽  
Rahul Annabathula ◽  
Shaojing Ye ◽  
Yuri M Klaychkin ◽  
Ahmed Abdel-Latif ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Myocardial Damage ◽  
Extramedullary Hematopoiesis ◽  
Heart Cell ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Hematopoietic Stem ◽  
Coronary Syndrome

Ischemic myocardial damage triggers leukocytosis, particularly the production of monocytes and neutrophils from the bone marrow and spleen (myelopoiesis). These cells infiltrate the evolving myocardial wound, degrade extracellular matrix, and aid in the clearance of dead cardiac myocytes and their debris. Although this inflammatory process is a prerequisite for tissue healing, it is non-specific and often blunt. If unchecked, excessive production of monocytes and neutrophils may result in abnormal ventricular remodeling and heart failure. The myocardial cellular and molecular events that orchestrate with the BM/spleen to regulate myelopoiesis remain unclear. We report here that the number of circulating monocytes and neutrophils peak within 24 hours following coronary artery ligation (LAD) in mice. This is due to expansion and proliferation of hematopoietic stem and multi-potential progenitor cells (HSPC) in the BM as well as extramedullary hematopoiesis in the spleen. MI induced-myelopoiesis was associated with a dramatic increase in the expression of S100a8/a9 (a damage associated molecular pattern), its receptor (Tlr4), the Nlrp3 inflammasome, and pro-IL1β in the heart. Cell separation studies revealed that the infiltrating neutrophils and cardiac fibroblasts are the predominant source of S100a8/a9 and the Nlrp3 inflammasome respectively in the heart. Furthermore, deletion of S100a8/a9 not only reduced MI-induced myelopoiesis but also significantly improved the mortality and cardiac function in mice following LAD. These data supports our hypothesis that neutrophil-derived S100a8/a9 interact with Tlr4 on cardiac fibroblasts to induce the Nlrp3 inflammasome and produce IL1β, which in turn stimulates IL-1R on HSPCs to promote myelopoiesis. Pharmacological strategies aimed at inhibition of S100a8a/9 or the Nlrp3 inflammasome-mediated production of IL1β may be a promising approach to limit inflammation following acute coronary syndrome.

Abstract 365: Targeted Delivery of IGF-1 Following Acute Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Raffay S Khan ◽  
Jay C Sy ◽  
Milton Brown ◽  
Mario D Martinez ◽  
Niren Murthy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Targeted Delivery ◽  
Coronary Artery Ligation ◽  
Nuclear Staining ◽  
Post Injection ◽  
Artery Ligation ◽  
Intact Cells ◽  
Double Stranded Dna

During acute myocardial infarction (MI) there is excessive necrosis of myocardial cells, leading to the release of large amounts of DNA, representing a potential target for drug delivery. Hoechst, a commonly used molecule for staining nuclei, binds to the minor groove of double-stranded DNA and can be functionalized to contain reactive groups such as free amines, sulfhydryls, and biotin moieties. Insulin-like growth factor-1 (IGF-1), a small molecule with a short half-life is protective immediately following MI, though there is potential for long-term toxicity and off-target effects. Therefore, we hypothesized that conjugating IGF-1 to Hoechst would increase targeting of IGF-1 to the injured myocardium. Hoechst-IGF1 (H-IGF1) was synthesized by binding Hoechst-biotin to biotinylated IGF-1 via a fluorescent streptavidin linker. Intact cells did not show nuclear staining with H-IGF1, while permeabilized cells had a significant increase in blue fluorescent Hoechst staining, indicating H-IGF1 was cell impermeable but could still bind DNA. Activity of H-IGF1 was demonstrated by Akt phosphorylation in cultured cardiac progenitor cells and was similar to native IGF-1. To determine in-vivo targeting of H-IGF1 to MI, mice underwent 30 minutes of coronary artery ligation followed by reperfusion (I/R). Six hours following MI, mice were injected intravenously with 70ng of H-IGF1, S-IGF1 (streptavidin bound IGF-1 only) or PBS followed by in vivo imaging at 30 and 120 minutes post-injection. At 30 minutes post-injection, we found 3.2% (2.2 of 70ng) of the injected dose of H-IGF1 in infarcted hearts compared with 1.8% (1.3 of 70ng) of S-IGF1 (n=5-7; p<0.05). To confirm that targeting of H-IGF1 was dependent on binding DNA, H-IGF1 pre-bound to double-stranded DNA was injected intravenously after I/R. This led to a significant (p<0.05) decrease in targeted IGF-1 levels. IGF-1 levels determined by ELISA 2 hours post-injection demonstrated a similar trend with increased targeting of H-IGF1 compared with S-IGF1 treated mice (4.2±0.6 ng vs. 2.4±0.2 ng; p<0.05). In conclusion, our data demonstrate that intravenous delivery of Hoechst-conjugated IGF-1 increases myocardial targeting. This provides a novel strategy for delivery of growth factors for the treatment of MI.

Abstract 866: Secreted Frizzled Related Protein 2 Modulates Post Myocardial Infarct Remodeling by Inhibiting Collagen Maturation through the Inhibition of Bone Morphogenetic Protein 1 Activity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Wei He ◽  
Lunan Zhang ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Myocardial Infarction ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Myocardial Infarct ◽  
Primary Cultures ◽  
The United States ◽  
Coronary Artery Ligation ◽  
Related Protein ◽  
Artery Ligation

Myocardial infarction and post-infarction remodeling with heart failure are the major cause of mortality and morbidity in the United States. We recently reported that intracardiac implantation of genetically engineered mesenchymal stem cell (MSC) overexpressing the Akt gene dramatically reduced the infarct size and restored cardiac functions in rodent hearts after coronary artery ligation. Further, we identified Secreted Frizzled Related Protein 2 (sfrp2) as a key factor released by Akt-MSC mediating myocardial survival and repair. However, the underlying mechanism remains elusive. Bone Morphogenetic Protein1 (BMP1)/Tolloid (TLD)-like metalloproteinases belong to a subgroup of astacin family and play key roles in the regulation of extracelluar matrix (ECM) formation and cardiac fibrosis. These proteases have procollagen C-proteinase (PCP) activities which are responsible for the cleavage of C-propeptides from procollagen precursors to produce mature collagen fibrils. In this report, we showed that three days following myocardial infarction in rats, both BMP1 protein expression and activity were upregulated in the infarcted left ventricle. Interestingly, we found recombinant sfrp2 could inhibit BMP1 activity in MI tissue samples as measured by an in vitro PCP activity assay. Furthermore, using purified recombinant proteins, we demonstrated that sfrp2, but not sfrp1 or sfrp3, inhibited BMP-1 activity in vitro. Moreover, purified sfrp2 could physically interact with BMP1 protein as shown by the co-immunoprecipitation assay. To provide further evidence that sfrp2 can interfere with collagen processing, we demonstrated that exogenously added sfrp2 interfered with procollagen processing in primary cultures of cardiac fibroblast culture medium. Similar results were obtained when these cells were transiently transfected with sfrp2 expressing plasmids. In summary, our data suggest that one of the molecular mechanisms underlying the cardioprotective and repair effects of sfrp2 protein on myocardial infarction is through the inhibition of BMP-1 activity. Therefore, sfrp2 has the potential clinical application as a novel anti-fibrotic reagent for the modulation of cardiac remodeling after acute myocardial infarction.

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