Inhibition of ADAMTS1 and ATP citrate lyase attenuates connexin-43 degradation and HFrEF

Human genome- and transcriptome-wide analyses revealed that 56% of heart failure cases have unknown causes. Interestingly, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is one of those causes. Previously, we have shown a robust increase in the degradation of a disintegrin and metalloproteinase (ADAM) and connexin-43 (Cx43) in human end-stage heart failure with reduced ejection fraction (HFrEF). We also observed Cx43 degradation and blood-heart barrier leakage during HFrEF in mice. Although Cx43 coordinates mitochondrial fusion-fission with myocyte contraction-relaxation, respectively, the mechanism is unclear. Interestingly, inhibition of mitochondrial ATP citrate lyase (ACYLi, a lipid-lowering agent) causes HFpEF, but its role in HFrEF is unknown. We hypothesize that during HFrEF, activation of ADAMTS1 degrades Cx43, causing dyssynchronous endothelial-myocyte-mitochondrial contraction coupling, as well as myocyte slippage during contraction and HFrEF. Because HFrEF is more prevalent in males than females, we created chronic cardiopulmonary volume overload by aorta-vena cava fistula (AVF) below the kidney in male wild-type (C57BL/6J) mice aged 12 weeks. By serial echocardiography, we observed HFrEF after 16 weeks. The ADAMTS1 inhibitor (epigallocatechin gallate) or ACYLi (hydroxycitric acid lactone) was administered in drinking water at the same time as AVF. Also, to assess interoceptive inhibition via Piezo channels, we ganglionally denervated the heart prior to AVF. By gel-specific substrate zymography, we measured NGAL, MMP2, MMP9, ADAMTS1, ADAMTS14, and TMPRSS2. The levels of Cx43, ADAMTS1, mitochondrial Drp1 (fission protein), and ACYL were measured by Western blot analysis. The results suggest that ADAMTS1 is activated during HFrEF. Connexin-43 degradation and mitochondrial mitophagy were increased by an increase in Drp1. The therapeutic effects of ADAMTS1 and ACYL inhibitors for systolic HFrEF are suggested.