Inhibition of specific phospholipases and kinases prevents cardiomyocyte death and calcium overload induced by activated fatty acid derivatives in a rat model.
Targeting these pathways may mitigate fatty acid-induced cardiomyocyte injury; extends mechanistic insights in rat models but leaves open clinical translation.
Ten to fifty micromoles of palmitoyl-L-carnitine (PC) or myristoyl-D,L-carnitine (MC) evoke a high-amplitude elevation of cytosolic calcium level ([Ca 2+ ] i ), hypercontraction and cell death in the primary culture of rat ventricular myocytes. The lag period of this effect varies within 2–8 min and depends on the mitochondrial capacity to accumulate Ca 2+ . Maximal level of Ca 2+ , attainable at the end of the lag period, depends on calcium concentration in the external medium and is mediated by plasma membrane nonspecific permeability. Preincubation of cardiomyocytes with the inhibitors of phospholipase C, cytosolic phospholipase A 2 and/or Ca 2+ /calmodulin-dependent protein kinase II prevents cell death, increases lag period duration and reduces maximal [Ca 2+ ] i . Both PC and MC, even at low concentrations (1–5 μM), dramatically increase the frequency of Ca 2+ -sparks and Ca 2+ -waves in cardiomyocytes and promote the formation of sustained microdomains with elevated calcium concentration. We discuss possible mechanisms of Ca 2+ -microdomain formation, where the “vicious circle” of Ca 2+ -dependent phospholipases activation may arise. The “vicious circle” with combined autocatalytic action of Ca 2+ -dependent phospholipases may be implicated in hydrolysis of membrane phosphatidylcholine and subsequent induction of nonselective permeability for Na + and Ca 2+ (lipid pore).
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Berezhnov et al. (2010) studied this question.
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