Role of phospholipases in cytosolic calcium overload and cardiomyocytes death in response to activated fatty acid derivatives

Ten to fifty micromoles of activated fatty acid derivatives palmytoyl carnitine (PC) or myristoyl carnitine (MC) evoke a high-amplitude elevation of cytosolic Ca²⁺ 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⁺. Here we report that maximal [Ca²⁺]_i at the end of the lag period depends on calcium concentration in the external medium and is mediated by plasma membrane nonspecific ion permeability. Preincubation of cardiomyocytes with phospholipase C, cytosolic phospholipase A2, and/or Ca²⁺/calmodulin-dependent kinase II inhibitors before PC or MC application prevents cell death, increases lag period and reduces maximal [Ca²⁺]_i Both PC and MC dramatically increase the frequency Of Ca²⁺ sparks and Ca ²⁺ 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 Ca ²⁺-dependent phospholipase activity arises. The vicious circle leads to hydrolysis of phosphatidylcholine in plasma membrane and subsequent induction of nonselective permeability for Na⁺ and Ca²⁺.