The potential role of sphingolipid-mediated cell signaling in the interaction between hyperglycemia, acute myocardial infarction and heart failure

Abstract

Pharmacological and genetic activation of enzymes controlling key sphingolipids synthesis, such as sphingosine-1-phosphate, increases insulin sensitivity in rodents and increases myocardial tolerance to ischemia. Major projects are being realized to develop clinical strategies to manipulate sphingolipid metabolism in this clinical settings, with the ultimate goal of increasing insulin sensitivity and augmenting myocardial tolerance to ischemia. Thus, a clear understanding of the sphingolipid-mediated signaling in ischemic heart disease is required to devise strategies to develop novel agents and technologies that directly target this signaling pathway.

Sphingosine-1-phosphate signalling as a therapeutic target for patients with abnormal glucose metabolism and ischaemic heart disease

“…18 Role of sphingosine-1-phosphate signalling Sphingolipids are ubiquitous components of the lipid bilayer of eukaryotic cells consisting of a head group attached to ceramide. 8 Ceramide is synthesized de novo or formed by the degradation of sphingolipids, such as sphingomyelin. 8 Ceramide can be further deacylated to sphingosine, which can then be phosphorylated by sphingosine kinases, forming S1P.…”

“…8 Ceramide is synthesized de novo or formed by the degradation of sphingolipids, such as sphingomyelin. 8 Ceramide can be further deacylated to sphingosine, which can then be phosphorylated by sphingosine kinases, forming S1P. 8 Ceramide may serve as a second messenger and as a precursor to other second messengers such as S1P.…”

“…8 Ceramide can be further deacylated to sphingosine, which can then be phosphorylated by sphingosine kinases, forming S1P. 8 Ceramide may serve as a second messenger and as a precursor to other second messengers such as S1P. Evidence suggests that levels of ceramide are increased by a variety of cell stressors, and when ceramides increase, the cell can initiate apoptosis, whereas increases in S1P levels generally promote cell survival and proliferation.…”

“…21 Within the cardiovascular system, S1P mediates cardioprotection following ischaemia-reperfusion injury, anti-inflammatory response, endothelial function, inhibition of oxidation, and synthesis of nitric oxide and prostacyclin (PGI 2 ), which have some antiatherothrombotic properties. 8 Apart from its cardiovascular effects, the S1P pathway may have roles in signalling cascades controlling host responses to infection, as exemplified by Machesky et al 23 in their human cytomegalovirus study showing that S1P may promote both the viral replication and the survival of the virus-infected cells. 22,23 S1P signalling may also play a critical role in cancer progression, including cell transformation/oncogenesis, cell migration/metastasis, and tumour microenvironment neovascularization.…”

“…[5][6][7] These complex relationships between cardiovascular disorders and abnormalities in glucose tolerance are thought to be multifactorial, but there is growing evidence to suggest that sphingolipids may play an important role in this relationship. 8 Sphingosine-1-phosphate (S1P) is a bioactive signalling molecule which modulates insulin signalling. 9,10 S1P is released by cardiac tissue during ischaemic stress or as a consequence of inflammation.…”