Abstract. Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.

No abstract

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the reninangiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI 2 in renovascular hypertension in vivo, employing mice lacking the PGI 2 receptor (IP -/-mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP -/-mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP -/-mice than in WT mice. All these parameters were measured in mice lacking the four PGE 2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI 2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP -/-mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP -/-mice. These results indicate that PGI 2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.

1 Eects of the prostanoids on the growth of cultured aortic vascular smooth muscle cells (VSMCs) were examined using mice lacking prostanoid receptors. 3 In VSMCs from wild-type mice, expressions of mRNAs for the EP 4 and TP were most abundant, followed by those for the IP, EP 3 and FP, when examined by competitive reverse transcriptase-PCR. Those for the EP 1 , EP 2 and DP, however, could not be detected. 4 AE1-329, an EP 4 agonist, and cicaprost, an IP agonist, inhibited platelet derived growth factor (PDGF)-induced proliferation of VSMCs from wild-type mice; these inhibitory eects disappeared completely in VSMCs from EP 4 7/7 and IP 7/7 mice, respectively. In accordance with these eects, AE1-329 and cicaprost stimulated cAMP production in VSMCs from wild-type mice, which were absent in VSMCs from EP 4 7/7 and IP 7/7 mice, respectively. 5 Eects of PGE 2 on cell proliferation and adenylate cyclase were almost similar with those of AE1-329 in VSMCs from wild-type mice, which disappeared in VSMCs from EP 4 7/7 mice. 6 PGD 2 inhibited PDGF-induced proliferation of VSMCs from both wild-type and DP 7/7 mice to a similar extent. This action of PGD 2 was also observed in VSMCs from EP4 7/7 and IP 7/7 mice. 7 In VSMCs from wild-type mice, I-BOP, a TP agonist, showed potentiation of PDGF-induced hypertrophy. I-BOP failed to show this action in VSMCs from TP 7/7 mice. 8 The speci®c agonists for the EP 1 , EP 2 or EP 3 , and PGF 2 a showed little eect on the growth of VSMCs. 9 These results show that PGE 2 , PGI 2 and TXA 2 modulate PDGF-induced proliferation or hypertrophy of VSMCs via the EP 4 , IP and TP, respectively, and that the inhibitory eect of PGD 2 on PDGF-induced proliferation is not mediated by the DP, EP 4 or IP.