Hypertrophy Of Noninfarcted Myocardium Research Articles

366 Abrogation of S100B Expression in S100A1 Deficient Mice Improves Survival Post Myocardial Infarction

Post-myocardial infarction (MI) ventricular remodeling involves ventricular dilation, hypertrophy of non-infarcted myocardium, myocyte apoptosis, the induction of S100B and the downregulation of S100A1. Whereas S100A1 deficiency results in cardiac functional impairment and high early mortality post-MI, abrogation of S100B preserves cardiac function in the setting of augmented hypertrophy post-MI. To assess the consequences of S100B expression in S100A1 knock out (KO) mice, wild-type (WT), S100A1 KO, S100B KO and S100A1-B KO 6-8 week-old mice were subjected to 35 days after left anterior descending coronary artery ligation with similar age-matched sham-operated controls. S100A1-B KO mice demonstrated better survival as compared to S100A1 KO and WT mice (79.5% vs. 28.6% vs. 69.7 % respectively, p<0.05), comparable to S100B KO mice (82.6%). Most of the deaths in S100A1 KO mice occurred 3-6 days following MI. Acute hemodynamic monitoring post-MI demonstrated that the S100A1 KO animals died of rapidly of progressive pump failure. At day 2 post-MI, S100A1 KO mice demonstrated S100B expression, increased left ventricular dilatation by echocardiography, less collagen I and III mRNAs within the infarct area, an increase in MMP-9 expression and apoptosis (as assessed by Caspase-3 activity and TUNEL staining) in the infarct border zone of versus WT. Among survivors at day 35, post mortem examination indicated that the WT and KO groups of infarcted mice mounted a hypertrophic response that was augmented in the S100B KO and S100A1-B KO groups (WT 3.95±0.21; S100A1 KO 4.05±0.13; S100B KO 4.39±0.18; S100A1-B KO 4.71±0.21 mg/g Body Weight, p<0.05 S100A1-B KO vs. S100A1 KO). The augmented hypertrophic response in the S100B KO and S100A1-B KO groups was associated with less apoptosis (as assessed by Caspase-3 activity) compared to the WT and S100A1 KO mice (WT 52.5±5.4; S100A1-KO 58.6±6.9; S100B KO 41.6±3.7; S100A1-B KO-43.8±3.5 µmol/mL, p<0.05 S100A1-B KO vs. S100A1 KO). The post infarct left ventricular end diastolic pressure was lower in S100A1-B KO and S100B KO mice compared to WT and S100A KO mice (S100A1-B KO 6.1±0.4 vs. S100A1KO 12.1±1.9 mmHg, p<0.05). Our results suggest that the abrogation of S100B expression in S100A1-B KO mice augmented hypertrophy, decreased apoptosis, preserved extracellular matrix proteins and was beneficial to the preservation of cardiac function and survival within this time frame.

301 Abrogation of S100B expression in S100A1 deficient mice improves survival post myocardial infarction

Post-myocardial infarction (MI) ventricular remodeling involves ventricular dilation, hypertrophy of non-infarcted myocardium, myocyte apoptosis, the induction of S100B and the downregulation of S100A1. Whereas S100A1 deficiency results in cardiac functional impairment and high early mortality post-MI, abrogation of S100B preserves cardiac function in the setting of augmented hypertrophy post-MI.

Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo

Mitofusin-2 (Mfn2) suppresses smooth muscle cell proliferation through inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2) pathway. Since the ERK1/2 pathway is implicated in mediating hypertrophic signaling, we studied the changes in Mfn2 in cardiac hypertrophy using in vitro and in vivo models. Phenylephrine was used to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). In vivo hypertrophy models included spontaneously hypertensive rats (SHR), pressure-overload hypertrophy by transverse aortic constriction (TAC), hypertrophy of non-infarcted myocardium following myocardial infarction (MI), and cardiomyopathy due to cardiac-restricted overexpression of β2-adrenergic receptors (β2-TG). We determined hypertrophic parameters and analysed expression of atrial natriuretic peptide (ANP) and Mfn2 by real-time PCR. Phosphorylated-ERK1/2 (phospho-ERK) was measured by Western blot. Mfn2 was downregulated in phenylephrine treated NRCMs (by ∼40%), hypertrophied hearts from SHR (by ∼80%), mice with TAC (at 1 and 3 weeks, by ∼50%), and β2-TG mice (by ∼20%). However, Mfn2 was not downregulated in hypertrophied hearts with 15 weeks of TAC, nor in hypertrophied non-infarcted myocardium following MI. phospho-ERK1/2 was increased in hypertrophied myocardium at 1 week post-TAC, but not in non-infarcted myocardium after MI, indicating that downregulated Mfn2 may be accompanied by an increase of phospho-ERK1/2. This study shows, for the first time, downregulated Mfn2 expression in hypertrophied hearts, which depends on the etiology and time course of hypertrophy. Further study is required to examine the causal relationship between Mfn2 and cardiac hypertrophy.

Neutralization of interleukin-1β in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling

OBJECTIVESWe sought to examine the role of the pro-inflammatory cytokine, interleukin-1-beta (IL-1β), in the process of left ventricular (LV) remodeling in the early phase after myocardial infarction (MI).BACKGROUNDStudies have shown that pro-inflammatory cytokines are closely related to the progression of LV remodeling after MI.METHODSMice underwent coronary artery ligation, and the time course of LV remodeling was followed up to 20 weeks. The gene expression level of IL-1β was examined. In a second set of experiments, the mice underwent coronary artery ligation followed by treatment with anti–IL-1β antibody (100 μg, intravenously), versus control immunoglobulin G (100 μg, intravenously) immediately after the operation.RESULTSRapid hypertrophy of noninfarcted myocardium was observed by four weeks, and interstitial fibrosis progressed steadily up to 20 weeks. Anti–IL-1β treatment increased the occurrence of ventricular rupture and suppressed collagen accumulation in the infarct-related area. At four and eight weeks after the operation, total heart weight and LV end-diastolic dimension were significantly greater in the anti–IL-1β-treated mice than in the other groups. In the infarct-related area, collagen accumulation was suppressed, whereas in the noninfarcted area, pro-collagen gene expression levels, particularly type III, were decreased in the anti–IL-1β-treated mice.CONCLUSIONSAnti–IL-1β treatment suppressed pro-collagen gene expression and delayed wound healing mechanisms—properties that are likely to lead to progression of LV remodeling. In the acute phase of MI, IL-1β appears to play a protective role.

Usefulness of plasma brain natriuretic peptide after acute myocardial infarction in predicting left ventricular dilatation six months later

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are synthesized and secreted from the ventricular myocardium after the onset of myocardial infarction (MI), and plasma concentrations of ANP and BNP are significantly correlated with hemodynamic variables and residual left ventricular (LV) function. 1‐4 Furthermore, plasma concentrations of these peptides may be used as simple biochemical predictors of prognosis after MI. 5,6 LV dilatation after MI may occur due to expansion of the infarct site, 7 hypertrophy of noninfarcted myocardium, or maladaptive LV “ remodeling.” 8,9 We hypothesized that plasma natriuretic peptide concentration correlated with LV remodeling. We studied the relation between plasma natriuretic peptide concentrations 1 month after the onset of MI and LV dilatation.

Differential Expression of Voltage-Gated K + Channel Genes in Left Ventricular Remodeled Myocardium After Experimental Myocardial Infarction

Left ventricular (LV) remodeling after experimental myocardial infarction (MI) is associated with hypertrophy of noninfarcted myocardium and electrophysiological alterations. We have recently shown that post-MI hypertrophied LV myocytes have prolonged action potential duration (APD) and generate triggered activity from early afterdepolarizations. The prolonged APD was attributed to decreased density of the two outward K+ currents, I(to)-fast (I(to)-f) and I(to)-slow (I(to)-s), rather than changes in the density and/or kinetics of the L-type Ca2+ current. The changes in ionic current density may be related to alterations in the expression and levels of ion channel proteins. To test this hypothesis, rats underwent either left anterior descending coronary artery (LAD) ligation (post-MI group [n = 10]) or sham surgery (sham group [n = 10]). Three weeks later transcripts from the noninfarcted LV myocardium in the post-MI group (n = 6) and LV myocardium of the sham group (n = 6) were analyzed by RNase protection assay. Expressions of five K+ channel subunit mRNAs (Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2) reported in the rat ventricle were analyzed. Compared with the sham group, expressions of Kv1.4, Kv2.1 (putative I(to)-s), and Kv4.2 (putative I(to)-f) channel subunit mRNAs were significantly decreased by 60% (P < .03), 54% (P < .005), and 53% (P < .002), respectively, in the post-MI group. There was no significant change in the Kv1.2 and Kv1.5 mRNA levels. Western blotting demonstrated a similar decrease in the Kv2.1 and Kv4.2 immunoreactive protein levels (43% [P < .03] and 67% [P < .003], respectively [n = 4]) and no significant change in Kv1.5 immunoreactive protein level. Our results strongly correlate with the electrophysiological findings in this model and show that transcriptional regulation in the post-MI remodeled rat LV is distinct for each voltage-gated K+ channel subunit. These findings provide, at least in part, the molecular basis for the electrophysiological alterations observed in this model.

Sex difference in development of hypertrophy of noninfarcted myocardium and its mechanismin rats

Sex difference in development of hypertrophy of noninfarcted myocardium and its mechanismin rats