Role of phospholipases in cytosolic calcium overload and cardiomyocytes death in the presence of activated fatty acid derivatives

Ten to fifty micromoles of palmitoyl-L-carnitine (PC) or myristoyl-D,L-carnitine (MC) evoke a high-amplitude elevation of cytosolic calcium level ([Ca²⁺]_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 Ca²⁺. Maximal level of Ca²⁺, 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 A₂ and/or Ca²⁺/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 Ca²⁺-sparks and Ca²⁺-waves in cardiomyocytes and promote the formation of sustained microdomains with elevated calcium concentration. We discuss possible mechanisms of Ca²⁺-microdomain formation, where the "vicious circle" of Ca²⁺-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 Ca²⁺ (lipid pore).