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Polycystin-1 Protects Against DNA Damage and Atrial Fibrillation
Abstract
Atrial Fibrillation (AF) is the most common cardiac arrhythmia with a 1 in 4 lifetime risk. AF impairs cardiac function and increases the risk of thrombi, heart attack, and stroke. Although common and harmful, little is known about the molecular mechanisms driving this disease. As such, current therapeutics to treat AF are non-specific and have poor therapeutic profiles. Patients with Polycystin 1 (PC1) mutations have an increased risk of AF. Recent evidence demonstrates that AF can be induced by increased DNA damage, along with its’ previously demonstrated roles in action potential duration and calcium (Ca^2+) handling. Interestingly, PC1 has been shown, in ventricular cardiomyocytes, to play a role in action potential duration, Ca^2+ handling. Unexpectedly, extensive evidence presented in this doctoral work suggest that PC1 protects against atrial DNA damage.
This study’s overarching hypothesis was that PC1 regulates atrial cardiomyocyte function and susceptibility to atrial arrhythmias. Here, we sought to test this hypothesis and elucidate the molecular mechanisms driving these alterations. First, we studied whether disruption of PC1 in animal models increases AF susceptibility and found increased rates of AF compared to controls in a cardiomyocyte-specific PC1 KO mice and a preclinical mouse model harboring a PC1 knock-in mutation (R3227C). We then demonstrated that atrial cardiomyocytes have impaired Ca^2+ handling and shortened action potential duration. Finally, we identified that PC1 regulates the DNA damage response and leads to increase DNA damage susceptibility which results in altered Ca^2+ wave propagation. This research is the first to identify PC1’s role in AF susceptibility and that DNA damage plays a role in PC1 induced atrial cardiomyocyte dysfunction.
Citation
Hendrickson, Troy (2023). Polycystin-1 Protects Against DNA Damage and Atrial Fibrillation. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /198825.