J Lipid Atheroscler.  2020 Jan;9(1):23-49. 10.12997/jla.2020.9.1.23.

Sphingolipid Mediators of Myocardial Pathology

• Kovilakath A
• Cowart LA

• KMID: 2470799
• DOI: http://doi.org/10.12997/jla.2020.9.1.23

Abstract

Cardiomyopathy is the leading cause of mortality worldwide. While the causes of cardiomyopathy continue to be elucidated, current evidence suggests that aberrant bioactive lipid signaling plays a crucial role as a component of cardiac pathophysiology. Sphingolipids have been implicated in the pathophysiology of cardiovascular disease, as they regulate numerous cellular processes that occur in primary and secondary cardiomyopathies. Experimental evidence gathered over the last few decades from both in vitro and in vivo model systems indicates that inhibitors of sphingolipid synthesis attenuate a variety of cardiomyopathic symptoms. In this review, we focus on various cardiomyopathies in which sphingolipids have been implicated and the potential therapeutic benefits that could be gained by targeting sphingolipid metabolism.

Keyword

Sphingolipids; Cardiomyopathy; Cardiomyocytes; Ceramides; Sphingosine-1-phosphate receptor

MeSH Terms

Cardiomyopathies
Cardiovascular Diseases
Ceramides
In Vitro Techniques
Metabolism
Mortality
Myocytes, Cardiac
Pathology*
Receptors, Lysosphingolipid
Sphingolipids
Ceramides
Receptors, Lysosphingolipid
Sphingolipids

Figure

• 

  Fig. 1 Overview of sphingolipid structure and metabolism. (A) From left to right; DHS d18:0 sphingoid base, ceramide d16:1/16:0, DHC d18:0/16:0 and S1P d18:1. (B) The blue arrow indicates sulfatides, green arrows indicate the globosides and the orange arrows indicate the gangliosides. DHS, dihydrosphingosine; DHC, dihydroceramide; S1P, sphingosine-1-phosphate; DHS1P, dihydrosphingosine 1-phosphate; GalCer, galactosylceramide; SM, sphingomyelin; GlcCer, glucosylceramide.

• 

  Fig. 2 Summary of the signaling pathways of S1P and ceramide in the various types of cardiac hypertrophy. Activation is indicated with arrows, inhibition by perpendicular lines, black indicates known pathways, blue or red indicate potential pathways. S1P, sphingosine-1-phosphate; VEGF, vascular endothelial growth factor; Spns2, spinster 2; T3, triiodothyronine; S1PR1, sphingosine-1-phosphate receptor 1; TNFR, tumor necrosis factor receptor; eNOS, endothelial nitric oxide synthase; PP2A, protein phosphatase 2; Pak1, p21-Activated kinase 1; PKC, protein kinase C; HDAC, histone deacetylases; ASK1, apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; BAX, B-cell lymphoma 2 associated X protein; KLF4, Kruppel-like factor 4; HCM, hypertrophic cardiomyopathy; SphK, sphingosine kinase; NOX2, NADPH oxidase 2; ROS, reactive oxygen species; DbCM, diabetic cardiomyopathy; RYR1, ryanodine receptor 1.

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