Targeting the ALCAT1 enzyme for the treatment of pressure-overload hypertrophy.

AIMS: Pressure overload-induced heart failure is a major cause of fatality in patients with heart diseases. At present, there exists no highly effective treatment for this incapacitating condition. Cardiolipin (CL) is a mitochondrial specific phospholipid that plays an essential role in cardiac health. Depletion of tetralinoleoyl CL (TLCL), the signature CL species, is implicated in human and animal models of heart failure. We investigated whether pathological CL remodelling by lysocardiolipin acyltransferase-1 (ALCAT1) promotes the progression of left ventricular (LV) hypertrophy induced by pressure overload by depleting TLCL in the heart and underlying molecular mechanisms.

METHODS AND

RESULTS

We identified a remarkable causative role of ALCAT1 in promoting the development of pressure overload hypertrophy in a mouse model of heart failure by transverse aortic constriction (TAC). We show that ALCAT1 expression in the heart is dramatically upregulated by TAC. Consequently, deletion or inhibition of ALCAT1 through targeted genetic manipulation or pharmacological intervention with Dafaglitapin (Dafa), a highly potent and specific small molecular inhibitor, effectively mitigates pressure overload hypertrophy and its related pathogenesis, including cardiomyopathy, cardiac dysfunction, inflammation, and fibrosis by preventing mitochondrial dysfunction in the heart. Furthermore, ablation or inhibition of ALCAT1 not only restores TLCL level but also mitochondrial function and the related signal transduction pathways underlying these disorders, including mTORC1 signalling, oxidative stress, inflammation, and apoptosis in the heart of TAC mice.

CONCLUSION

In summary, these findings identified ALCAT1 not only as a key mediator of mitochondrial aetiology of pressure overload-induced heart failure but also a novel drug target for hypertensive heart failure and Dafa as a potential treatment for the disorder.