ADAMTS1 and ATP citrate lyase inhibition attenuate connexin-43 degradation and myocyte-myocyte slippage during systolic HFrEF

Previously, in human, we have shown the role of a dis-integrin and
metalloproteinase (ADAM) in connexin-43 (Cx43) degradation in human heart
end stage heart failure (i.e., heart failure with reduced ejection
fraction, HFrEF). We also observed Cx43 degradation and blood heart
barrier (BHB) leakage during HFrEF in mice. Although Cx43 coordinates
mitochondrial fusion-fission with myocyte contraction-relaxation,
respectively, the mechanism is unclear. Interestingly, a mitochondrial ATP
citrate lyase inhibition (ACYLi, a lipid lowering agent) mitigated HFpEF,
its role in HFrEF is unknown. We hypothesize that during HFrEF activation
of ADAMTS1 degrades Cx43, causing dyssynchronous
endothelial-myocyte-mitochondrial contraction coupling, and myocytes
slippage during contraction and HFrEF. Because HFrEF is more prevalent in
males than females, we created chronic cardio-pulmonary volume overload by
aorta-vena-cava fistula (AVF) below the kidney in male WT (C57BL/6J) mice
of 12-wks old. By serial ECHO, we observed HFrEF after 16-wks. The ADAMTS1
inhibitor (epigallocatechin gallate (EG)) or ACYLi (hydroxycitric acid
lactone) were administered in drinking water at same time of AVF. Also, to
determine the interoceptive inhibition by Piezo channels, we ganglionic
de-nervated the heart prior to AVF. By in gel specific substrate
zymography, we measured, NGAL, MMP-2, -9, ADAMTS1, ADAMTS14, and TMPRSS2.
The results suggest activation of ADAMTS1 during HFrEF. The connexin-43
degradation and mitochondrial mitophagy by increase in Drp1 were
increased.