Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway.

Bone morphogenetic protein (BMP) signaling regulates embryonic development of many organ systems and defective BMP signaling has been implicated in adult disorders of many of these systems. However, its relevance in cardiac disease has not been reported. Here we demonstrate for the first time that Bmp4 activity promotes cellular apoptosis following ischemia-reperfusion (I/R) injury induced myocardial infarction (MI). Bmp4 heterozygous null mice (Bmp4(+/)(-)) demonstrated reduced infarct size, less myocardial apoptosis and down-regulation of pro-apoptotic proteins relative to wild-type mice following I/R injury. This was associated with reduction in I/R induced BMP4 levels in the left ventricular infarcted region. Furthermore, treatment of neonatal cardiomyocytes with BMP4 resulted in time and dose-dependent increase in cellular apoptosis and activation of the JNK MAP kinase pathway. In contrast, while JNK activation was significantly attenuated in Bmp4(+/)(-) mice and following Smad1 inhibition in myocytes, inhibition of JNK with a specific inhibitory peptide, TAT-JBD(20,) blocked BMP4 induced apoptosis. In vivo treatment of mice with Noggin, an endogenous extracellular BMP antagonist, or dorsomorphin, a small molecule inhibitor of BMP signaling, reduced infarct size, and inhibited pro-apoptotic signaling accompanied by an inhibition of Smad1 phosphorylation and JNK activation. These studies identify a novel role for Bmp4 in the pathogenesis of myocardial infarction and illustrate the use of a small molecule inhibitor of BMP signaling for treatment of acute I/R injury.

Timecourse of recovery after surgical intraperitoneal implantation of radiotelemetry transmitters in rats.

INTRODUCTION: Rats are used in drug safety because they satisfy regulatory guidelines, there is a large historical database, and their cardiovascular systems respond similarly to humans. The use of radiotelemetry offers a variety of advantages over non-invasive techniques. Implantation of telemetry devices for cardiovascular assessments in rats is not novel, but the time to recover from the surgery has not been reported. In order to assess this, mean arterial blood pressure (MAP), heart rate (HR), body temperature (BT), body weight (BW), food consumption (FC), activity, and general health were determined in male Sprague-Dawley rats for 2 weeks following surgery. METHODS: Radiotelemetry transmitters (TL11M2-C50-PXT, Data Sciences International, St. Paul, MN) were implanted into the peritoneal cavity of 15 rats under isoflurane anesthesia; 11 rats were used in the study. Data were collected (500 Hz for 24 h) using PONEMAH Physiology Platform software (Gould Instruments, Inc, Valley View, OH, version 4.0) on days 3, 8 and 15 following surgery. Body weight and 24-h food consumption were recorded 1 day prior to surgery and on days 3, 8 and 15 post-surgery; general health was recorded daily. RESULTS: MAP tended to be greater on day 3 (104+/-2 mmHg) than on days 8 or 15 (99+/-2 mmHg and 99+/-2 mmHg, respectively). By contrast, activity (arbitrary units) tended to be lower on day 3 (1.9+/-0.2) than on days 8 or 15 (2.9+/-1.2 and 3.0+/-1.0, respectively). HR ( approximately 460 bpm) and BT ( approximately 37.5 degrees C) remained constant throughout the study. FC on day 4 postsurgery was less than pre-surgery (16.7+/-6.6 g vs. 23.6+/-1.2 g) and returned by day 9 (23.6+/-5.4 g). BW on day 4 (295+/-20 g) was not different from presurgery (297+/-11 g) and the rats gained weight on subsequent days. There were no effects on overall appearance and behavior due to surgery. DISCUSSION: It is concluded that male Sprague-Dawley rats recover from surgery and can be used approximately 1 week following intraperitoneal implantation of radiotelemetry transmitters with monitoring of body weight and food consumption.