PI3K(p110α) as a determinant and gene therapy for atrial enlargement in atrial fibrillation

Abstract

Atrial fibrillation (AF) is an irregular heart rhythm, characterised by chaotic atrial activation, which is promoted by remodelling. Once initiated, AF can also propagate the progression of itself in the so-called ‘‘AF begets AF’’. Several lines of investigation have shown that signalling molecules, including reactive oxygen species, angiotensin II, and phosphoinositide 3-kinases (PI3Ks), in presence or absence of cardiovascular disease risk factors, stabilise and promote AF maintenance. In particular, reduced cardiac-specific PI3K activity that is not associated with oncology is cardiotoxic and increases susceptibility to AF. Atrial-specific PI3K(p110α) transgene can cause pathological atrial enlargement. Highlighting the crucial importance of the p110α protein in a clinical problem that currently challenges the professional health care practice, in over forty (40) transgenic mouse models of AF (Table1), currently existing, of which some of the models are models of human genetic disorders, including PI3K(p110α) transgenic mouse model, over 70% of them reporting atrial size showed enlarged, greater atrial size. Individuals with minimal to severely dilated atria develop AF more likely. Left atrial diameter and volume stratification are an assessment for follow-up surveillance to detect AF. Gene therapy to reduce atrial size will be associated with a reduction in AF burden. In this overview, PI3K(p110α), a master regulator of organ size, was investigated in atrial enlargement and in physiological determinants that promote AF.Table 1Gene AlterationAtrial enlargementFibrosisThrombusVentricular dysfunction based on echo and/or catheterConduction abnormalities by ECGAPD AlterationAF pattern/other major cellular and molecular mechanismsReferences[58][59]Atrial and ventricle APD70,oreduced triadin, RYR2, diastolic Ca2+, and Ca2+ transient amplitude[60]Cardiac-specific SR-located Ca2+-binding proteinAPD90, phase 4 ↑oreduced SR Ca2+ content, Ca2+ transient amplitudeoincreased ICa,L[61]AMPK TGN488I[62]A1AR TGCardiac-specific overexpression of A1 adenosine receptor (A1AR) with α-MHCAPD90, phase 4 ↔ APD50,APD70,[63]A3tg TGCardiac-specific overexpression of A3 adenosine receptor (A3AR) with α-MHC promoter[64][65][66]Kir2.1 TGKir2.1 IK1 channel subunit cardiac-specific overexpression with α-MHC promoterAPD90, phase 4 ↓APD50,APD75,MAP50,[67]Kcne1−/−K+-channel KCNE1 subunit global protein deletion in mouseAPD50, phase 2 ↓APD90, phase 4 ↓[68]APD50,APD90, phase 4 ↓oIncreased IKs density[69]Des−/−[70][71]APD25,APD50,APD90oLeaky SR Ca2+ stores[72]Human cAMP- CREM and reduced RyR2-S2814A phosphorylation heart-directedAPD80, phase 4 ↑oincreased SR Ca2+ leak and CaMKII activity[73][74][75]Anxa7−/−oβ1-adrenergic signalling[76]APD75oimpaired Ca2+ loadingoreduced intracellular Ca2+ transients[77][78][79]Nup155±APD90, phase 4 ↓[80]a1D−/−L-type Ca2+ channel (Cav1.3) subunit global knockoutolack of Cav1.3, and reduced ICa,L[81]LTCC (α1D−/−)L-type Ca2+ channel α1D subunit global knockoutoreduced ICa,L, Ca2+ transient amplitude, and SR Ca2+ content[82]oaltered expression of metabolic genes and K+ channels[16]Dct−/−APD50, phase 2 ↔ APD90, phase 4 ↔ [83]RyR2R176Q/+APD50 phase 2 ↔ APD80 phase 4 ↔ oelevated SR Ca2+ leak[84]Gαq TGAPD80, phase 4 ↑[85]NppaCre+Pitx2−/−APD20 phase 1, ↔ APD50 phase 2, ↔ APD90 phase 4, ↔ [86]AnkB±APD90 phase 4, ↓oreduced ICa,L[87]D1275N-Nav1.5Nav1.5 global missense mutationAPD50, phase 2 ↑APD90, phase 4 ↑oreduced peak INaoincreased late INa[88]SLN−/−APD50, phase 2 ↔ APD90, phase 4 ↑oSR Ca2+ overloadoincreased phosphorylation of RyR2[89]FKBP12.6−/−APD30, phase 2 ↔ APD50, phase 2 ↔ oSR Ca2+ leakoincreased INCXoCaMKII phosphorylation of RYR2 and PLB[90]MHC-TGFcys33serAPD80, phase 4 ↓ for both left and right atriaoincreased Ca2+ transient[91][92]Casq2−/−APD80, phase 4↑[93][94]F1759A-Nav1.5-dTGNav1.5 cardiac-specific expression with α-MHC promoterAPD80, phase 4 ↑ for both right and left atriaoincreased late INaoNCX regulation of Na+ entry[95][96][97]Mouse models that have been used to study the pathophysiology of AF, including atrial enlargement, electrophysiological alterations, apoptosis, functional and molecular underpinnings, and anatomical, transgenic; RYR2, ryanodine receptor 2; SR, sarcoplasmic reticulum; APD, action potential; SERCA mRNA, sarco/endoplasmic reticulum Ca2+-ATPase messenger ribonucleic acid; CTR, calcitonin receptor; KCNE1, potassium voltage-gated channel subfamily E member 1; AV, Atrioventricular block; MAP, monophasic action potential; PLB, phospholamban; ANP, atrial natriuretic peptide; β-AR, beta adrenergic receptor; PPβ1, protein phosphatase type 1β; NADPH, nicotinamide adenine dinucleotide phosphate; CaMKII, Ca2+/calmodulin-dependent protein kinase II; NCX, sodium–calcium exchanger; SERCA2a, Sarco/endoplasmic reticulum calcium (Ca2+) ATPase gene; TGF- β, Transforming growth factor beta; BNP, brain natriuretic peptide; HSP70, heat shock protein 70; DCM, dilated cardiomyopathy; AMPK, 5' adenosine monophosphate-activated protein kinase; PLK2, polo-like kinase 2; OPN, osteopontin; ERK1/2, extracellular signal-regulated kinase ½. ↔ unchanged in that condition; ✔ present in that condition; ↑ increased in that condition; ↓ reduced in that condition.