Bempedoic acid, an ATP-citrate lyase inhibitor, prolongs the golden therapeutic window via modulating myocardial energy metabolism in rats with uncontrolled hemorrhagic shock

ATP-citrate lyase (ACLY), a pivotal hub enzyme mediating the remodeling of cellular energy metabolism, and its specific inhibitor, bempedoic acid (BA), has been shown to exert multi-organ protective effects in models of ischemic injury and metabolic disorders. This study aims to determine whether BA could prolong the golden therapeutic window and exert multi-organ protection in a rat model of uncontrolled hemorrhagic shock (UHS), and to explore its underlying mechanisms.

A total of 208 SPF-grade SD rats (8 to 10 weeks old, weighing 180 to 220 g, half male and half female) were subjected. A rat UHS model was established by deep cutting the splenic parenchyma, with successful modeling defined as a mean arterial pressure (MAP) decrease to 40 mmHg. ①Forty-eight rats were randomly divided into a lactated Ringer’s solution (LR) group, a 10 mg/kg BA group (10 mg/kg BA + LR), and a 20 mg/kg BA group (20 mg/kg BA+LR), with 16 animals in each group. Hypotensive resuscitation was initiated immediately after successful modeling to maintain MAP at 50 to 60 mmHg. Blood pressure profiles, blood loss rate, infusion volume, and duration of maintained hypotension were recorded. ② Ninety-six rats were randomly divided into (n=24): a Sham group, a UHS group, a LR group, and a BA group (20 mg/kg BA+LR). After successful modeling, the UHS group received no resuscitation, while the other 2 groups underwent immediate hypotensive resuscitation. In 1 h later, the splenic artery was ligated for definitive hemostasis, followed by definitive fluid therapy with LR equivalent to twice the total blood loss volume. Outcome measurements included survival status, blood gas parameters, hepatic, renal and intestinal blood perfusion, biomarkers of vital-organ injury, pulmonary and cerebral water contents, myocardial contractile function, as well as myocardial levels of free fatty acid (FFA) and adenosine triphosphate (ATP).

① In the LR group, MAP was stably maintained within 50 to 60 mmHg for approximately 60 min, whereas both 10 and 20 mg/kg BA combined with LR solution sustained the target blood pressure for more than 180 min. Compared with the LR group, the 20 mg/kg BA group exhibited a significantly lower blood loss rate (63.7%±12.8% vs 73.8%±4.4%, P<0.05) and reduced infusion volume [(6.8±4.9) vs (18.7±9.8) mL, P<0.05]. The mean duration of maintained hypotension in the LR group was (57±17) min, with a 1-hour maintenance rate of 68.8%, and all animals died within 80 min. The mean hypotension-maintenance durations were extended to (138±60) min in the 10 mg/kg BA group and (157±50) min in the 20 mg/kg BA group, with 3-hour maintenance rates of 50.0% and 68.7%, respectively. ② The blood loss rate in the LR group was markedly higher than that in the UHS group [(55.6%± 6.3%) vs (48.4%±5.3%), P<0.05]. The BA group demonstrated a significantly lower blood loss rate compared with the LR group (47.2%±6.0%, P<0.05), along with a markedly reduced infusion volume [(4.5± 2.9) vs (15.7±6.4) mL, P<0.05], and the 72-hour survival rate increased from 12.5% to 25.0% (P<0.05). Compared with the LR group, BA intervention resulted in significant improvements in blood gas parameters including hemoglobin (Hb) and arterial partial pressure of oxygen (PaO₂) (P<0.05), and restored hepatic, renal and intestinal blood perfusion close to normal levels (P<0.05). BA treatment also mitigated cardiac, hepatic and renal injuries, with significantly decreased levels of cardiac troponin I (cTnI) and alanine aminotransferase (ALT) (P<0.05), while no significant difference was observed in pulmonary and cerebral water contents. Serum cTnI levels were significantly lower in the BA group than the LR group (P<0.05). Cardiomyocyte contraction amplitude in the LR group recovered to only 25.8% of the normal level, whereas BA treatment restored it to 54.6% of normal (P<0.05). Compared with the UHS group, the LR group showed no significant improvement in myocardial tissue FFA and ATP levels, whereas the BA group exhibited significantly decreased myocardial FFA levels and increased ATP content (both P<0.05).

The ACLY inhibitor BA effectively prolongs the golden therapeutic window in UHS rats. Its mechanism may be related to improving systemic oxygenation, restoring visceral perfusion, and enhancing myocardial ATP content to reverse energy metabolic disturbance, thereby alleviating myocardial and hepatic-renal function injuries and ultimately improving the 72-hour survival rate.