Dichloroacetate Ameliorates Cardiac Dysfunction Caused by Ischemic Insults Through AMPK Signal Pathway—Not Only Shifts Metabolism

Abstract

Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), regulates substrate metabolism in the heart. AMP-activated protein kinase (AMPK) is an age-related energy sensor that protects the heart from ischemic injury. This study aims to investigate whether DCA can protect the heart from ischemic injury through the AMPK signaling pathway. Young (3-4 months) and aged (20-24 months) male C57BL/6J mice were subjected to ligation of the left anterior descending coronary artery (LAD) for an in vivo ischemic model. The systolic function of the hearts was significantly decreased in both young and aged mice after 45 min of ischemia and 24 h of reperfusion. DCA treatment significantly improved cardiac function in both young and aged mice. The myocardial infarction analysis demonstrated that DCA treatment significantly reduced the infarction size caused by ischemia/reperfusion (I/R) in both young and aged mice. The isolated-cardiomyocyte experiments showed that DCA treatment ameliorated contractile dysfunction and improved the intracellular calcium signal of cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. These cardioprotective functions of DCA can be attenuated by inhibiting AMPK activation. Furthermore, the metabolic measurements with an ex vivo working heart system demonstrated that the effects of DCA treatment on modulating the metabolic shift response to ischemia and reperfusion stress can be attenuated by inhibiting AMPK activity. The immunoblotting results showed that DCA treatment triggered cardiac AMPK signaling pathway by increasing the phosphorylation of AMPK's upstream kinase liver kinase B1 (LKB1) under both sham operations and I/R conditions. Thus, except from modulating metabolism in hearts, the cardioprotective function of DCA during I/R was mediated by the LKB1-AMPK pathway.

Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines

“…It must be taken into account that DCA can target other cellular pathways in addition to PDK. Indeed, it has been reported that DCA affects the CoA biosynthetic pathway [42], activates the AMPK signaling pathway [43], antagonizes with acetate [44], and disturbs the tyrosine catabolism [45]. Moreover, comparison of the metabolite profiles in cells treated with DCA or more selective novel inhibitors of PDK resulted in different outcomes [46].…”

The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury

“…DCA is known to be neurotoxic when high doses, above 500 mg/kg, are used, or if 300 mg/kg is administered for more than 10 weeks [73,74]. However, many previous animal studies have confirmed the beneficial effects of administering DCA at dose of 50 to 200 mg/kg [75,76,77,78,79], and our previous study also confirmed that treatment with a dose of 100 mg/kg after ischemia reduced neuronal death [26]. According to the paper by Stacpoole, it was noted that DCA was rapidly absorbed following treatment, crosses the blood-brain barrier and activates PDH within a few minutes [80].…”

AMPK: a balancer of the renin–angiotensin system

“…The concept that the activation of AMPK is beneficial to various diseases has been widely recognized [56][57][58]. It has been proved that activating AMPK can improve cardiometabolic disease [7], protect from myocardial ischemia [7], inhibit cardiac hypertrophy and cardiomyopathy [8,[59][60][61], protect heart function and delay heart failure [7,[62][63][64][65], and antiarrhythmia [10]. Additionally, the decreased activity of AMPK has also been shown to participate in hypertension [48,66], lipid metabolism, inflammation [58], obesity, insulin resistance, type 2 diabetes [67], renal pathophysiology, aging [68], and tumor [68,69].…”