Mitochondria as a drug target in ischemic heart disease and cardiomyopathy

Abstract

Ischemic heart disease is a significant cause of morbidity and mortality in Western society. Although interventions, such as thrombolysis and percutaneous coronary intervention, have proven efficacious in ischemia and reperfusion injury, the underlying pathological process of ischemic heart disease, laboratory studies suggest further protection is possible, and an expansive research effort is aimed at bringing new therapeutic options to the clinic. Mitochondrial dysfunction plays a key role in the pathogenesis of ischemia and reperfusion injury and cardiomyopathy. However, despite promising mitochondria-targeted drugs emerging from the laboratory, very few have successfully completed clinical trials. As such, the mitochondrion is a potential untapped target for new ischemic heart disease and cardiomyopathy therapies. Notably, there are a number of overlapping therapies for both these diseases, and as such novel therapeutic options for one condition may find use in the other. This review summarizes efforts to date in targeting mitochondria for ischemic heart disease and cardiomyopathy therapy and outlines emerging drug targets in this field.

Figure 1. Mitochondrial pathologic events in IR injury

During ischemia, lack of O₂ inhibits Ox-Phos, diverting the glycolytic end product pyruvate to lactate, resulting in cellular acidification. Disposal of acid via the Na⁺/H⁺ exchanger (NHE) brings Na⁺ into the cytosol. This Na⁺ is exported via the Na⁺/Ca²⁺ exchanger (NCX) causing cytosolic Ca²⁺ overload, which is exacerbated by low ATP disabling Ca²⁺ export by ATPases. Inhibited Ox-Phos is the primary cause of low ATP. Mitochondrial Ca²⁺ uptake is minimal due to low ΔΨ_m, and both acidic pH and accumulation of NADH keeps the PT pore closed. At reperfusion, rapid re-establishment of Ox-Phos and ΔΨ_m results in mitochondrial Ca²⁺ overload and ROS generation. Together with normalization of pH, this triggers PT pore opening, leading to cell death. In surviving cells, ROS activates mitochondrial uncoupling (H⁺ leak), which inhibits ATP synthesis, exacerbating the metabolic crisis. Oxidation of cardiolipin (CL) also occurs, along with nucleotide loss (both NADH from mitochondria and ATP from the cell). ROS damage to ANT contributes to low ATP levels. For full explanation see text.(Illustration Credit: Ben Smith).

Figure 2. Cardioprotective signaling: all roads lead to mitochondria

IPC either directly or indirectly (via G-protein coupled receptors or growth factor receptors) activates numerous protein kinases and other cell signaling molecules, including the generation of ROS for signaling purposes. These signals filter through a limited number of downstream mediators including: (i) eNOS generation of NO^•, (ii) phosphorylation and inhibition of GSK-3β, (iii) changes in metabolism (iv) activation of mitophagy. At the mitochondrial level, many of these signals converge on the opening of mK_ATP and mBK channels, and the activation of H⁺ channels, both of which inhibit the PT pore directly, or inhibit the events leading up to its opening. Volatile anesthetics also trigger mitochondrial K⁺ channel opening and recruit many of the same kinase signals as IPC. Other drugs such as statins can also activate kinases in the RISK pathway. Together, these events inhibit cell death during subsequent IR injury. See text for more details. (Illustration Credit: Ben Smith).