Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered.

Enhanced synthesis of a specific matrix metalloproteinase, MMP-2, has been demonstrated in experimental models of ventricular failure and in cardiac extracts from patients with ischaemic cardiomyopathy. Cultured neonatal rat cardiac fibroblasts and myocytes were used to analyse the determinants of MMP-2 synthesis, including the effects of hypoxia. Culture of rat cardiac fibroblasts for 24 h in 1 % oxygen enhanced MMP-2 synthesis by more than 5-fold and augmented the MMP-2 synthetic responses of these cells to endothelin-1, angiotensin II and interleukin 1β. A series of MMP-2 promoter-luciferase constructs were used to map the specific enhancer element(s) that drive MMP-2 transcription in cardiac cells. Deletion studies mapped a region of potent transactivating function within the 91 bp region from k1433 to k1342 bp, the activity of which was increased by hypoxia. Oligonucleotides from this region were cloned in front of a heterologous simian-virus-40 (SV40) promoter and mapped the enhancer activity to a region between k1410 and k1362 bp that included a potential activating protein 1 (AP-1)-binding sequence, C −"$*% CTGACCTCC. Site-specific mutagenesis of the core TGAC sequence (indicated in bold) eliminated the transactivating activity within the k1410 to k1362 bp sequence. Electrophoretic mobility shift assays (EMSAs) using the k1410

Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKC⑀ knockout mouse hearts. Am J Physiol Heart Circ Physiol 282: H1970-H1977, 2002. First published February 14, 2002 10.1152/ajpheart.01029.2001.-Sphingosine-1-phosphate (S1P) protects neonatal rat cardiac myocytes from hypoxic damage through unknown signaling pathways. We tested the hypothesis that S1P-induced cardioprotection requires activation by the ⑀-isoform of protein kinase C (PKC⑀) by subjecting hearts isolated from PKC⑀ knockout mice and wild-type mice to 20 min of global ischemia and 30 min of reperfusion. Pretreatment with a 2-min infusion of 10 nM S1P improved recovery of left ventricular developed pressure (LVDP) in both wild-type and PKC⑀ knockout hearts and reduced the rise in LV end-diastolic pressure (LVEDP) and creatine kinase (CK) release. Pretreatment for 2 min with 10 nM of the ganglioside GM-1 also improved recovery of LVDP and suppressed CK release in wild-type hearts but not in PKC⑀ knockout hearts. Importantly, GM-1 but not S1P, increased the proportion of PKC⑀ localized to particulate fractions. Our results suggest that GM-1, which enhances endogenous S1P production, reduces cardiac injury through PKC⑀-dependent intracellular pathways. In contrast, extracellular S1P induces equivalent cardioprotection through PKC⑀-independent signaling pathways.

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