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Background:Gene transfer of hepatocyte growth factor (HGF) is reported to protect the heart against ischemia- reperfusion injury. However, its precise mechanisms are unknown.Methods:In male Japanese white rabbits, 1 × 109particles of adenovirus Ad-HGF (HGF group, n=15) or adenovirus Ad-LacZ (control group, n=15) was directly injected into the myocardium. Three days after viral infection, the coronary artery was occluded for 30 min and reperfused. The heart was excised at 2 or 14 days after infarction. The infarct size and cardiac function were obtained. Bcl-2 protein was detected. Myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, were also measured.Results:The infarct size was significantly reduced in the HGF group (13.4 ± 2.3 %) than in the control group (36.5 ± 2.0 %) at 2 days after infarction. Smaller LV dimension and increased LV ejection fraction and higher capillary density assessed by immunostaining of CD31 were observed in the HGF group at 14-days after infarction. Bcl-2 protein was significantly increased at 4 h of reperfusion in the HGF group than in the control group. The 2,5-DHBA levels during ischemia and reperfusion was significantly attenuated in the HGF group compared to the control group.Conclusion:In vivo adenovirus-mediated HGF gene transfer improves cardiac function and remodeling via enhancing angiogenesis and Bcl-2 expression and decreasing hydroxyl radicals in a rabbit model of myocardial infarction.

Adult cardiac myocytes show a dynamic and unique process during execution of apoptosis; they exhibit beating just before and at the early phase of apoptosis (Am J Pathol. 2001), suggesting important roles of intracellular Ca2+concentration ([Ca2+]i) and Ca2+regulatory proteins for initiating apoptosis in those cells. In the present study, we examined the regulatory mechanisms of Ca2+regulatory proteins for initiating apoptosis in adult cardiac myocytes, which was induced by activation of β-adrenergic receptor by isoproterenol (10−5M). Apoptosis was evident, as documented by activated caspase-3, DNA fragmentation based on in situ nick end-labeling (TUNEL) and DNA ladder pattern, and apoptotic ultrastructure. These apoptotic features were found significantly inhibited by L-type Ca2+channel antagonist (nifedipine), SERCA antagonist (thapsigargin), and ryanodine receptor antagonist (ryanodine) in a dose-dependent manner. According to serial observation under a real-time videomicroscope, those antagonists inhibited not only apoptotic morphological change but also the pre-apoptotic beating. These findings suggest an important role of a fluctuation of [Ca2+]i - i.e., not only an increase in [Ca2+]i through L-type Ca2+channel or ryanodine receptor but also a decrease in it through SERCA, for initiating cardiac myocyte apoptosis, implying an exquisite regulation of initiating apoptosis in adult cardiac myocytes by multiple Ca2+regulatory proteins.

Background:Ca channel blockers are widely prescribed for the treatment of hypertension and coronary artery diseases. However, it is still unknown whether dihydropyridine Ca channel blockers are protective against arrythmias. We investigated whether cilnidipine, a N+L-type Ca channel blocker reduces the incidence of ventricular premature arrythmia during ischemia and reperfusion.Methods and Results:Forty Japanese white rabbits underwent 30 min ischemia and 30 min reperfusion. Cilnidipine (0.5 or 1.0 microgram/kg/min, i.v.), nifedipine (3.0 microgram/kg/min, i.v.) or saline was continuously during ischemia and reperfusion. Electrocardiogram and blood pressure were monitored and the incidences of ventricular premature beats (VPBs) during ischemia and reperfusion were measured. In other 21 rabbits, myocardial interstitial noradrenaline levels were determined before, during and after 30 min of ischemia with cilnidipine (1.0 microgram/kg/min, n=7), nifedipine (3.0 microgram/kg/min, n=7) or saline (n=7) using a microdialysis technique. The incidences of VPBs during ischemia and during reperfusion were significantly attenuated in the cilnidipine 0.5 and 1.0 groups but not in the nifedipine group compared to the control group. Myocardial interstitial noradrenaline levels were significantly reduced in the cilnidipine 1.0 group but not in the nifedipine group compared to the control. Conclusion:Cilnidipine but not nifedipine attenuates the incidence of ventricular premature beats during ischemia and reperfusion and this effect may be related to decreased cardiac sympathetic nerve activity in rabbits.

Background:There is controversy whether free radical scavengers reduce myocardial infarct size. Among many free radical scavengers, edaravone has been reported to be effective for the treatment of cerebral infarction. Therefore, we hypothesized that edarabon may also be effective for the treatment of myocardial infarction. Methods:Japanese white rabbits underwent a 30-min ischemia followed by a 48-hr or 14 day reperfusion. In the edaravone group, edaravone (a free radical scavenger, 3 mg/kg, i.v.) was administered at 10 min before reperfusion. In the control group, saline was administered at 10 min before reperfusion. The heart was excised 48 hours after reperfusion or 14 days after reperfusion. The risk area was determined by Evans blue dye and the infarct area was determined by TTC staining. The infarct size as a percentage of the risk area was obtained. Results:The infarct size as a percentage of the area at risk was significantly reduced in the edaravone group as compared with the control group both at 48 hours and 14 days after reperfusion. Smaller left ventricular (LV) dimension and increased LV ejection fraction at 14 days after infarction assessed by echocardiography were observed in the edaravone group than in the control group. Conclusion:Free radical scavenger edaravone reduces the infarct size and improves cardiac function and remodeling in rabbits.

Blockade of angiotensin II type 1A receptor (AT1) attenuates left ventricular remodeling and heart failure after myocardial infarction (MI). However, the morphological bases for such beneficial effects are not fully elucidated except for prevention of fibrosis in the noninfarcted area. AT1 knockout (KO) mice, compared with wild-type (WT) mice, showed significantly attenuated left ventricular remodeling (dilatation) and dysfunction comprised of excessive fibrosis in noninfarcted area at 4 weeks after large MI, consistent with the earlier studies. Morphometry revealed that the size of infarct scar was comparable between each group, but that the infarct wall thickness was greater while its coronal expansion was less marked in AT1KO mice. The cell population in infarct scar was greater in AT1KO mice, where extravascular a-smooth muscle actin (SMA)-positive cells were abundant. In 1 week-old infarct consisting of granulation tissue, apoptosis of a-SMA-positive cells was less frequent in AT1KO mice than in WT mice while proliferating activity of them was similar between the groups. Thus, in AT1KO mice, the survived myofibroblasts might have contributed to infarct contraction and infarct wall thickening, which consequently altered infarcted tissue geometry to reduce wall stress, and then prevented left ventricular dilatation and dysfunction. Unfavorable infarct tissue dynamics may be an important mechanistic basis for deleterious effects of AT1 signals upon the postinfarction disease process.