Abstract
The obesity-related 16 kDa peptide leptin is synthesized primarily in white adipocytes although its production has been reported in other tissues including the heart. There is emerging evidence that leptin may contribute to cardiac pathology especially that related to myocardial remodelling and heart failure. In view of the importance of mitochondria to these processes, the goal of the present study is to determine the effect of leptin on mitochondria permeability transition pore opening and the potential consequence in terms of development of apoptosis. Experiments were performed using neonatal rat ventricular myocytes exposed to 3.1 nM (50 ng/ml) leptin for 24 hours. Mitochondrial transition pore opening was analyzed as the capacity of mitochondria to retain the dye calcein-AM in presence of 200 µM CaCl2. Leptin significantly increased pore opening although the effect was markedly more pronounced in digitonin-permeabilized myocytes in the presence of calcium with both effects prevented by the transition pore inhibitor sanglifehrin A. These effects were associated with increased apoptosis as evidenced by increased TUNEL staining and caspase 3 activity, both of which were prevented by the transition pore inhibitor sanglifehrin A. Leptin enhanced Stat3 activation whereas a Stat 3 inhibitor peptide prevented leptin-induced mitochondrial transition pore opening as well as the hypertrophic and pro-apoptotic effects of the peptide. Inhibition of the RhoA/ROCK pathway prevented the hypertrophic response to leptin but had no effect on increased pore opening following leptin administration. We conclude that leptin can enhance calcium-mediated, Stat3-dependent pro-apoptotic effects as a result of increased mitochondrial transition pore opening and independently of its hypertrophic actions. Leptin may therefore contribute to mitochondrial dysfunction and the development of apoptosis in the diseased myocardium particularly under conditions of excessive intracellular calcium accumulation.
Highlights
Leptin, the product of ob/ob gene is an important adipocytederived satiety factor whose plasma levels are profoundly increased in obesity in direct proportion to the degree of adiposity [1]
In both intact myocytes as well as digitonin-permeabilized myocytes, the effect of leptin was prevented by the mitochondrial permeability transition pore (mPTP) inhibitor sanglifehrin A (SfA)
Our results suggest that fludarabine is more selective as a Stat1 inhibitor compared to Stat3, this agent produced no effect on the increased mPTP opening seen following leptin addition (Figure 3E) in contrast to the effect seen with Stat3 inhibitor peptide (SIP)
Summary
The product of ob/ob gene is an important adipocytederived satiety factor whose plasma levels are profoundly increased in obesity in direct proportion to the degree of adiposity [1]. Leptin exerts a myriad of effects through its cell surface receptors termed ObR or LepR, of which there are six isoforms which belong to the class 1 cytokine receptor family [8]. These receptors are upregulated in the human failing myocardium [9]. Leptin has recently been shown to increase myocardial collagen levels concomitant with diastolic dysfunction when administered to obese ob/ob mice [16]. Others have shown a salutary role of leptin receptor deletion in the postinfarcted heart [17] as recently discussed [18], the bases for such differences are not well understood
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