Mitochondria as a Drug Target in Ischemic Heart Disease and Cardiomyopathy

Department of Anesthesiology, Box 604, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642. .
Circulation Research (Impact Factor: 11.02). 10/2012; 111(9):1222-36. DOI: 10.1161/CIRCRESAHA.112.265660
Source: PubMed


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.

    • "The mechanism of cardioprotection, though unclear, may involve mild uncoupling of the mitochondrial membrane potential causing Ca 2+ overload and ROS generation. Mild swelling resulting from influx of K + into the mitochondria may also regulate the PT pore[107]. Mitochondrial potassium sensitive ATP channel (mKATP) also plays critical role in cardioprotection. Complex II is related to mKATP in such a way that complex II inhibitors open mKATP, and mKATP openers inhibit complex II[108]DC activation, maturation, and T cells activation by stimulated DCsincludes symptoms such as: (i) inhibition of respiratory complexes[112]and ANT[113], (ii) higher proton leak of the inner membrane[114], (iii) oxidation of CL and other associated membrane protein dysfunctions[115], (iv) excessive ROS generation[116], (v) opening of mPTP and consequent release of proteins such as cyt c[117], (vi) nucleotide depletion[118], and (vii) mitochondrial Ca 2+ overload (Fig. 9). "
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    ABSTRACT: Mitochondrial dysfunctions are recognized as major factors for various diseases including cancer, cardiovascular diseases, diabetes, neurological disorders, and a group of diseases so called “mitochondrial dysfunction related diseases”. One of the major hurdles to gain therapeutic efficiency in diseases where the targets are located in the mitochondria is the accessibility of the targets in this compartmentalized organelle that imposes barriers toward internalization of ions and molecules. Over the time, different tools and techniques were developed to improve therapeutic index for mitochondria acting drugs. Nanotechnology has unfolded as one of the logical and encouraging tools for delivery of therapeutics in controlled and targeted manner simultaneously reducing side effects from drug overdose. Tailor-made nanomedicine based therapeutics can be an excellent tool in the toolbox for diseases associated with mitochondrial dysfunctions. In this review, we present an extensive coverage of possible therapeutic targets in different compartments of mitochondria for cancer, cardiovascular, and mitochondrial dysfunction related diseases.
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    • "Exposure to VA preceding IR leads to activation of several signaling cascades that involve protein kinases and " small " transient ROS/RNS, including NO · . These signaling molecules eventually converge on mitochondria to provide protection (Zaugg et al., 2003b; Walters et al., 2012). Marinovic et al. (2006) provided evidence in support of a dual role mK ATP channels in VA protection, i.e., as a trigger to initiate the signaling cascade and as an effector responsible for the cardioprotective memory. "
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    ABSTRACT: Mitochondria are critical modulators of cell function and are increasingly recognized as proximal sensors and effectors that ultimately determine the balance between cell survival and cell death. Volatile anesthetics (VA) are long known for their cardioprotective effects, as demonstrated by improved mitochondrial and cellular functions, and by reduced necrotic and apoptotic cell death during cardiac ischemia and reperfusion (IR) injury. The molecular mechanisms by which VA impart cardioprotection are still poorly understood. Because of the emerging role of mitochondria as therapeutic targets in diseases, including ischemic heart disease, it is important to know if VA-induced cytoprotective mechanisms are mediated at the mitochondrial level. In recent years, considerable evidence points to direct effects of VA on mitochondrial channel/transporter protein functions and electron transport chain (ETC) complexes as potential targets in mediating cardioprotection. This review furnishes an integrated overview of targets that VA impart on mitochondrial channels/transporters and ETC proteins that could provide a basis for cation regulation and homeostasis, mitochondrial bioenergetics, and reactive oxygen species (ROS) emission in redox signaling for cardiac cell protection during IR injury.
    Full-text · Article · Sep 2014 · Frontiers in Physiology
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    • "Additional studies are necessary to further identify upstream signaling events, for instance whether the pyruvate carrier is directly regulated by nitrosation or PKG-mediated Fig. 6. Epicatechin (EPI) effects on neonatal rat ventricular cardiomyocyte (NRVM) respiration, extracellular acidification and respiration in the presence of α-cyano-4-hydroxycinnamic acid (CIN), etomoxir (ETO), of N-Nitro-L-arginine methyl ester (L-NAME) or 1H-[1] [2] [4]oxadiazolo[4,3-a]quinoxalin-1-1-one (ODQ). Oxygen consumption rate was measured in NRVM following addition of increasing doses of EPI using a XF24 extracellular flux analyzer. "
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    ABSTRACT: Background: Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated. Methods and results: Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2+ load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation. Conclusions: IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.
    Full-text · Article · May 2014 · International Journal of Cardiology
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