Transgenic Overexpression of Heart-specific Adenine Nucleotide Translocase 1 Positively Affects Contractile Function in Cardiomyocytes

Cellular Physiology and Biochemistry

关键词: Adenine nucleotide translocase;    Contraction-relaxation cycle;    Heart;    Cardiomyocytes;    Myofibrillar proteins;    Transgenic rat;   

DOI  :  10.1159/000325214

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims The adenine nucleotide translocase (ANT) exchanges ATP and ADP over the inner mitochondrial membrane, supplying the cells with energy. Interestingly, myocardial ANT1 overexpression preserves cardiac structure and function under pathophysiological conditions. To ascertain whether the contractile system is directly affected by increased ANT1 expression, we analyzed cell morphology, contraction and relaxation parameters of ANT1 transgenic (ANT1-TG) cardiomyocytes, myofibrillar protein expression, and Ca²⁺ handling in ANT1-TG rat hearts. Results ANT1-TG cardiomyoycytes displayed an elevation in cell volume (52.6±12.0%; p<0.0001) in comparison to wildtype (WT) cells. Concurrently, contractile function in ANT1-TG cells was significantly increased, measured by a decline in time to peak contraction (TTP) and RT50, the time from peak contraction to 50% relaxation, during stimulation with 0.5, 1, and 2 Hz. Quantification of myofibrillar proteins exhibited a marked increase in total cardiac myosin heavy chain (51.8±12.8%) (p<0.03), beta myosin heavy chain (22.9±5.0%; p<0.03), actin (23.8±8.8%; p<0.05), and troponin I (51.5±13.7%; p<0.01). Regarding intracellular Ca²⁺ handling, ANT1-TGs revealed a significant elevation in sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA2a) protein level (22.2±4.7%; p<0.01) associated with increased Ca²⁺ uptake into the SR (34%; p<0.01). Moreover, the plasmalemmal Ca²⁺ ATPase (PMCA) indicated advanced protein expression (23.8±4.8%; p<0.01), whereas the protein amount of the Na⁺/Ca²⁺ exchanger was not altered in ANT1 overexpressing hearts. Conclusion These data reveal a close association of elevated mitochondrial ATP/ADP transportation via ANT1 with increased contractile function. Furthermore, the ANT1-TGs exhibit an elevation in SR Ca²⁺ transport that contributes to increased cardiac work, which may protect the heart under pathophysiological conditions.

【 授权许可】

CC BY-NC-ND