Adrenomedullin gene delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion

Abstract

delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion. Am J Physiol Heart Circ Physiol 285: H1506-H1514, 2003. First published June 12, 2003 10.1152/ ajpheart.00270.2003 has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemiareperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide ]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the AktBad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.superoxide; Akt; Bax; p38 MAPK ADRENOMEDULLIN (AM) was first isolated from human pheochromocytoma tissue in 1993 (20) and has been identified in tissues relevant to cardiovascular and renal function, such as the adrenal medulla, kidney, heart, aorta, lung, and brain (14,35). AM is a potent vasodilator as intravenous administration of the AM peptide produced a hypotensive effect along with a marked reduction of total peripheral resistance in animals and humans (7,19). In addition to influencing the contractile state of blood vessels, AM also inhibits protein and DNA synthesis in cultured cardiac myocytes and fibroblasts, which is mediated via a cAMPdependent pathway (16). Transgenic mice overexpressing the AM gene under the control of the preproendothelin-1 promoter have reduced mean blood pressure (30). Nitric oxide (NO) synthase (NOS) inhibition normalizes blood pressure in these mice, indicating a role of NO/cGMP in mediating the AM effect. Embryos of AM-deficient mice die at midgestation with cardiovascular abnormalities, including overdeveloped ventricular trabeculae and underdeveloped arterial walls (3). Increased AM levels have been reported in the pathophysiology of cardiac diseases such as hypertension, cardiac hypertrophy, and heart failure (15, 17). Elevated AM production could be a biological attempt to compensate for cardiac and renal damage. These findings suggest important roles of AM in the development and f...

Adrenomedullin prevents apoptosis in prostate cancer cells

“…Importantly, in an in vivo rat model of ischemia and reperfusion, AM attenuates myocardial infarction and apoptosis [31]. This effect is caused through increase in Akt and Bad phosphorylation and Bcl-2 levels [31]. Our present results in prostate cancer cells also demonstrate that AM induces the expression of Bcl-2 and decreases Bax, which favours the anti-apoptotic signaling and prevents the cells from undergoing apoptosis.…”

“…Bcl-2 and AM are co-expressed in cervical cancer [30]. Importantly, in an in vivo rat model of ischemia and reperfusion, AM attenuates myocardial infarction and apoptosis [31]. This effect is caused through increase in Akt and Bad phosphorylation and Bcl-2 levels [31].…”

Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia

“…15 In a rat myocardial ischemia/reperfusion injury model, gene delivery of AM suppressed ROS production by NADPH oxidase inhibition via the nitric oxide (NO)-cGMP signaling pathway. 23 In addition, because AM induced vasodilation because of increased cAMP and NO overproduction 24 and endothelin-1 downregulation, 25 AM-induced reduction of shear stress might be involved in reducing ROS production. But we performed no hemodynamic studies.…”

Kallikrein/Kinin Protects against Myocardial Apoptosis after Ischemia/Reperfusion via Akt-Glycogen Synthase Kinase-3 and Akt-Bad·14-3-3 Signaling Pathways

“…Our previous study showed that systemic delivery of the kallikrein gene inhibited I/R-induced myocardial injury, which was accompanied by increased kinin and cGMP levels (22). Similarly, adrenomedullin gene transfer also increased cardiac cGMP levels after I/R (23). cGMP is an indicator of nitric oxide formation, and these results indicate that the nitric oxide-cGMP signaling cascade may serve as the common signaling cascade for cardioprotective stimuli in the injured myocardium.…”

“…Preparation of Replication-deficient Adenoviral Vectors-Adenoviral vector harboring the human tissue kallikrein cDNA (Ad.CMV-TK) under the control of the cytomegalovirus (CMV) enhancer/promoter or adenoviral vector alone (Ad.Null) were constructed and prepared as described previously (23). Adenoviruses containing the dominant-negative mutant of Akt (Ad.DN-Akt), constitutively active Akt (Ad.MyrAkt), catalytically inactive GSK-3␤ (Ad.GSK3␤-KM) and constitutively active mutant of GSK-3␤ (Ad.GSK3␤-S9A) were kindly provided by Dr. Kenneth Walsh, St. Elizabeth's Medical Center in Boston.…”