Loss of Polycystin-1 In Cardiac Myocytes is Associated with Increased Cell Death after Myocardial Ischemia/Reperfusion

Aims: Myocardial ischemia and reperfusion (I/R) results in cardiomyocytes death and ventricular dysfunction. Polycystin-1 (PC1) is a cardiomyocyte expressed mechanosensor whose absence causes cardiac dysfunction. This work aims to assess the role of PC1 in cardiomyocytes cell death induced by myocardial I/R.
Methods: PC1 knock out (KO) mice were subjected to both in situ and ex vivo myocardial I/R, using ligation of the left anterior descending artery for the first and isolating perfused hearts subjected to global ischemia for the second. Infarct size was assessed by triphenyltetrazolium chloride staining. PC1 knockdown neonatal rat ventricular myocytes (siPC1 NRVMs) were subjected to simulated I/R. Cell death was assessed by lactate dehydrogenase (LDH) activity and the rate of apoptosis was analyzed by immunodetection of caspases 3, 8, 9 and Bax levels.
Results: PC1 KO mice subjected to I/R show a larger infarction size and more LDH activity than control group. Also, siPC1 NRVMs present higher sensitivity to I/R induced cell death, showing more LDH activity and higher levels of cleaved caspase-3. Surprisingly, we found a significant activation of caspase-8 in siPC1 NRVMs after I/R, meanwhile caspase-9 and Bax levels were not affected in this model.
Conclusion: Here we show that PC1 loss increases I/R-induced cell death in three different models. PC1 actively participates in the survival of cardiomyocytes subjected to I/R, probably sensing the mechanical changes generated during I/R, and triggering signals that regulate cellular death processes such as necrosis and the extrinsic pathway of apoptosis.