Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110␣) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110␣) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult (ϳ4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice (ϳ15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF , suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110␣) and AF. (Am J Pathol

Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure

“…The inhibition of myocardial PI3K has the potential to induce cardiac dysfunction by decreasing cardiac contractility and increasing susceptibility to cardiac arrhythmias 28. Loss of PI3K activity is associated with prolonged APD and QT intervals, whereas an increase in its activity markedly decreases atrial fibrosis 29, 30. Therefore, PI3K, a cardioprotective protein, is associated with the development of AF.…”

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…Thus, new therapeutic strategies to protect the heart in the setting of diabetes are greatly needed. We have previously demonstrated that increased activation of phosphoinositide 3-kinase (PI3K)(p110α) in the heart is protective in pathological settings in which the heart is subjected to a localised cardiac insult such as aortic constriction (pressure overload) or coronary artery ligation (myocardial infarction) [12][13][14]. However, whether PI3K (p110α) can protect the heart against diabetic cardiomyopathy caused by global hyperglycaemia is unknown.…”

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

“…In brief, the model was generated by breeding a cardiac-specific Tg mouse with a failing heart because of dilated cardiomyopathy (DCM, induced with increased activity of mammalian sterile 20-like kinase 1, Mst1; a kinase activated by clinically important pathologic insults such as ischaemia/ reperfusion 21 ) with a cardiac-specific Tg mouse with reduced phosphoinositide 3-kinase (PI3K; because of expression of a dominant negative PI3K (dnPI3K) mutant 22 ). Risk factors for HF and AF, including ageing, obesity and diabetes, have been associated with insulin resistance that can lead to depressed/ defective PI3K signalling [23][24][25] , and PI3K activity was also depressed in atrial tissue from patients with AF 20 . Reducing PI3K in the mouse model with DCM accelerated the HF phenotype based on the following findings: additional systolic dysfunction, substantial atrial enlargement, increased fibrosis and elevated lung weights 20 .…”

“…Risk factors for HF and AF, including ageing, obesity and diabetes, have been associated with insulin resistance that can lead to depressed/ defective PI3K signalling [23][24][25] , and PI3K activity was also depressed in atrial tissue from patients with AF 20 . Reducing PI3K in the mouse model with DCM accelerated the HF phenotype based on the following findings: additional systolic dysfunction, substantial atrial enlargement, increased fibrosis and elevated lung weights 20 . At 4 months of age, the HF þ AF model was also associated with electrocardiogram (ECG) abnormalities including intermittent/episodic AF (irregular heart rhythm with loss of P waves confirmed by intracardiac ECG recordings) 20 .…”

“…We previously described a transgenic (Tg) mouse model with a failing heart, which is susceptible to AF (referred to here as HF þ AF model) 20 . In brief, the model was generated by breeding a cardiac-specific Tg mouse with a failing heart because of dilated cardiomyopathy (DCM, induced with increased activity of mammalian sterile 20-like kinase 1, Mst1; a kinase activated by clinically important pathologic insults such as ischaemia/ reperfusion 21 ) with a cardiac-specific Tg mouse with reduced phosphoinositide 3-kinase (PI3K; because of expression of a dominant negative PI3K (dnPI3K) mutant 22 ).…”