The Molecular And Cellular Mechanisms Of Acetaldehyde (ACA) Toxicity On Heart Is Involved In Disorder Of Intracellular Calcium Cycling

Alcoholic cardiomyopathy is one of the major causes of non-ischemic heart damage, and its exact pathogenesis has not been clearly revealed. There is evidence suggest that the underlying mechanism may include the toxicity from the first oxidized metabolic product of ethanol, namely acetaldehyde (ACA). This study is to observe the toxic effects of acetaldehyde on rat's heart in vivo and in vitro, and on ventricular myocytes. Thus revealed the role played by acetaldehyde in alcoholic cardiomyopathy in the pathogenesis. We observe the effect of acetaldehyde on rats overall indicator of myocardial mechanics in vivo and in vitro. And we are also using the whole-cell patch-clamp and ion imaging technique to observe the impact of acetaldehyde on cardiomyocytes L-type Calcium current and [Ca²⁺]_i. In addition, we evaluate the expression of calcium-regulating protein by molecular biology experiments. Our results suggest that, 120mg/kg acetaldehyde can add a significantly changes to the overall myocardial mechanics indicators and electrocardiogram. LVEDP increased from 0.088±0.0472 to 0.479±0.216; and ECG ST segment from 0.020±0.005 in the control group increased to the current level of 0.077±0.025. 30mM acetaldehyde can significantly inhibit the in vitro cardiac contraction; while 30mM acetaldehyde also enables the intracellular Ca²⁺ concentration significantly increased in ventricular myocytes. We found that by the use of blocker agent, acetaldehyde to increase intracellular calcium concentration was related to the role of PKC and PKA-mediated signaling pathway. The ACA also act an inhibitor of L-Ca²⁺ current. Further, through RT-PCR and Western Blot, we found acetaldehyde can change expression levels in several important Ca²⁺ regulate protein, such as SERCA2α, Na⁺/Ca²⁺ exchanger (NCX) and so on. The first time we have a systematic evaluation of the acetaldehyde toxicity on rat's heart. Experimental results suggest that, acetaldehyde has a direct toxic effect on the heart, its toxicity has a negative inotropic effect, and this negative inotropic effect may be related to intracellular Ca²⁺-cycle- disorders.