**2.2. Mitochondrial function and metabolism in the healthy heart**

#### *2.2.1. Cardiac metabolism*

While HF constitutes a complex syndrome of diseases, it generally refers to the inability of the heart to pump sufficient blood to the periphery. As such, historically HF has been studied as a disease of the left ventricle (LV), and most treatments for HF are designed to improve function of the failing LV. Hallmarks of current HF therapies include neurohormonal targets, vasodilators, and/or reducing heart rate- all of which should reduce myocardial oxygen consumption and workload and rebalance energy supply and demand in the heart. However, these therapeutic approaches are largely based on symptom management and have not significantly changed the clinical course of the disease, as the staggering HF morbidity and mortality statistics have remained largely the same over the past 15 years [3]. These data suggest new therapeutic strategies are needed for successful HF therapy, and targeting the bioenergetic deficit through restoration of mitochondrial abnormalities has recently emerged as a promis-

While LV-centered pathology constitutes the largest number of HF cases, it is ability of the right ventricle (RV) to function that predicts survival in many cardiovascular disease contexts including pulmonary hypertension [5], (which will be reviewed in much greater detail below), heart failure with preserved ejection fraction [6], and dilated cardiomyopathy [7]. However, no RV-directed therapies exist, and far less is known about the pathophysiology of the failing right heart than the LV. So, while considerable progress has been made to elucidate the metabolic and mitochondrial derangements that underlie LV failure, basic understanding of mitochondrial and metabolic derangements in RV dysfunction continues to be ill-defined. Here, we will present what is known about RV failure and the role of mitochondria and metabolism in models of experimental RV failure and in human populations with right HF. We believe successful HF therapies must target the failing RV for significant improvement in clinical and

Although many similarities exist between the ventricles, and they work in concerted effort to efficiently contract and relax for sufficient blood delivery, important embryological, physiological, and pathophysiological differences exist between the right and left ventricles [8]. We will briefly discuss a few of these differences, with a specific focus on mitochondria and

The RV and LV have different embryological origins and diverge early in development. The RV derives from the anterior (secondary) heart field, while the LV derives from the early heart tube (primary heart field) [9]. This early divergence is transcriptionally regulated, and several transcription factors have been identified which are responsible for the chamber-specific development including Hand2 and Tbx20 [10]. During gestation, the RV functions as the systemic pump. After birth, the RV becomes coupled to the low-pressure pulmonary circulation. As the ductus arteriosus and foramen ovale close, peripheral vascular resistance (PVR) decreases,

ing strategy [4].

4 Mitochondrial Diseases

therapeutic outcomes.

metabolism.

**2. The healthy right and left ventricles**

**2.1. Embryology, anatomy, and physiology**

In healthy states, the heart derives energy from multiple sources to match the demand of contractile function, and can serve as an energetic omnivore based on substrate availability. When given a choice, however, the heart prefers lipid, based on significantly higher ATP production per carbon molecule compared to glycolysis. The first report of the heart's preference for lipid was published in 1953 [14], with subsequent studies confirming that fatty acids constitute 60–90% of cardiac ATP sources with carbohydrates supplying the remaining 10–40% [15]. Fatty acids are transported into cardiomyocytes through fatty acid transporters and subsequently into the mitochondria by carnitine palmitoyltransferase-1 into the matrix where they undergo β-oxidation. The successive oxidation of fatty acid chains provides acetyl CoA that enters the Kreb's Cycle to produce energy to supply the demand of contraction. Glucose is transported into cardiomyocytes by facilitated diffusion mediated by glucose transporters GLUT1 and GLUT4 (insulin-dependent). Once inside the cell, glucose is phosphorylated by hexokinase as the first step in glycolysis. Nine steps later, pyruvate is either decarboxylated by pyruvate dehydrogenase (PDH) to form acetyl CoA to be transported into the mitochondria to begin Kreb's Cycle, or reduced to form lactate and subsequent anaerobic metabolism.

Assuming similar metabolism and mechanisms of control of these pathways between the ventricles might be overly simplistic. As discussed above, the RV is thinner and has a different shape than the LV, which contributes to differential responses to pathological load (discussed below). Transcriptional profiles, including those which regulate metabolism, differ between ventricles, as a comparative gene expression of mRNA and microRNA between control RV and LV samples identified numerous genes with differential expression between the ventricles [16]. These genes spanned a wide variety of biological processes including metabolism, with carbohydrate metabolism (three differentially expressed genes), lipid, fatty acid and steroid metabolism (11 genes), nucleic acid (30 genes) and protein metabolism (22 genes), as well as other metabolic genes (11 genes) significantly varying between ventricles [16].

#### *2.2.2. Mitochondrial content, dynamics, and function*

The heart is an extremely energetically active organ. Despite accounting for less than 1% of body weight, it consumes roughly 8% of total ATP [4]. The process of energy production and consumption is incredibly dynamic, as the heart only stores enough energy to supply a few beats and turns over the entire metabolite pool every 10 seconds [17]. To meet this costly energy demand, the heart is the most mitochondrially-dense tissue, with mitochondria comprising 25–30% of cardiac myocyte cell volume [18]. Mitochondria are responsible for the majority of ATP production in the healthy heart, with some estimates suggesting that close to 95% of cardiac ATP production occurs through mitochondrial oxidative phosphorylation [19]. Mitochondria are double membrane-bound organelles which are tightly regulated within the myocardium to facilitate efficient energy production. ATP is produced through oxidation of metabolic fuel to provide reducing equivalents (NADH and FADH<sup>2</sup> ) that are coordinately used to generate a proton motive force across the inner mitochondrial membrane to drive ATP synthesis. Successive electron transfer through complexes I through IV of the electron transport chain culminates in ATP synthesis through complex V (ATP Synthase) in an oxygen-dependent manner.

In addition to dynamically undergoing fission and fusion to regulate the mitochondrial network, mitochondrial turnover or biogenesis, creates new mitochondria. Mitochondria have their own DNA (mtDNA) and genetic code that is distinct from nuclear genetics. The biogenesis of mitochondria is a cooperative effort between mitochondrial and nuclear-encoded genes to synthesize all proteins which comprise the five electron transport chain complexes. Biogenesis is transcriptionally regulated by peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC-1α), the "master regulator" of biogenesis [29], transcription factor of mitochondria (TFAM), and nuclear respiratory factor 1 (NRF1) [30]. Biogenesis of mitochondria also requires the synthesis of cardiolipin, a mitochondrial-specific phospholipid located on the inner mitochondrial membrane which regulates respiratory enzyme super complex assembly [31]. The transcriptional assessments of TFAM, PGC-1α and NRF1 or markers of mitochondrial content are often used as surrogates of biogenesis, a cumulative process which is truly represented by net synthesis of mitochondrial proteins and/or lipids into functioning organelles [32]. Mitochondrial biology and physiology are further complicated when we consider the arrangement of mitochondrial populations within the adult heart. Three distinct cardiac populations have been identified: the subsarcolemmal mitochondria (SSM), located along the perimeter of the cell, interfibrillar mitochondria (IFM), located between the myofibrils [33], and perinuclear mitochondria which are arranged in clusters surrounding nuclei and are presumably involved with transcriptional activity. Although never directly tested, SSM are hypothesized to provide ATP for basic cell functions, whereas IFM provide energy for the contractile apparatus. The original description of IFM and SSM populations identified differences in biochemical and respiratory properties, as well as ultrastructural differences [33]. Following years of debate as to whether these two populations were different and discrepancy over the causal role of isolation procedures in obscuring differences, consensus seems to have been reached regarding important physiological differences in IFM and SSM. It should be noted that these differences have only been identified in LV mitochondria, and to our knowledge, subpopula-

Mitochondria and Metabolism in Right Heart Failure http://dx.doi.org/10.5772/intechopen.70450 7

Indeed, most of what we know about mitochondrial structure and function in the healthy heart derives from studies of the LV, and only a few studies have compared healthy right and left ventricles. However, a small report suggests differential expression of autophagy and mitophagy regulators in the RV compared to LV [34]. A proteomic analysis of healthy rabbit and porcine LV and RV free walls demonstrated similar cellular aerobic capacity, mitochondrial volume, mitochondrial electron transport chain content (complexes I, III, IV, and V), as well as mitochondrial enzyme activity [35]. Our group assessed mitochondrial content and electron transport chain activity, as well as protein markers of mitochondrial dynamics in the RV and LV from healthy 2-week old cows (**Figure 1**). While we generally found similar mitochondrial profiles between the ventricles, there were some subtle differences including higher relative copy number of COXI (mt/nDNA) and higher expression of Mfn1 in the RV compared to the LV. Together, the few published papers comparing the LV and RV and the data from our group suggest that though small or subtle, differences exist in mitochondrial physiology in the RV and LV, consistent with the different energetic and functional capacities of the ventricles. A more careful description of interventricular differences will aid in understanding pathological adaptations that occur within

these organelles, and the contribution they play in development of cardiac disease.

tions of SSM and IFM have never been described in the RV.

It has been recognized for quite some time that mitochondria exist in a dynamic reticulum and not as isolate organelles [20]. This network not only allows for efficient ATP production, but also facilitates mitochondrial quality control. The maintenance of this network occurs through continuous mitochondrial fusion and fission, a process mediated by both inner and outer mitochondrial membrane proteins. Fusion, the elongation of the mitochondrial network, increases mitochondrial mass and is regulated mainly by mitofusin-1 and mitofusin-2 (Mfn1 and Mfn2) of the outer mitochondrial membrane and optic atrophy-1 (Opa1) of the inner membrane. Fission, the fragmentation of the mitochondrial network, results in a greater number of smaller mitochondria, and is mediated in part by dynamin-related protein-1 (DRP-1) and fission protein 1 homolog (Fis1) [21]. Fusion and fission are critically necessary for cardiac development as loss of any of these proteins is embryonically lethal [22–24]. Substantial evidence suggests they are also important in the adult heart, as genetic manipulation of these proteins has profound impact on cardiac function.

In addition to regulating mitochondrial shape and size, mitochondrial fission and fusion proteins also regulate mitochondrial quality control through mediating mitophagy, the cellular process of removing damaged mitochondria through autophagy [25]. Autophagy, a highly conserved lysosomal-dependent process of removing damaged cargo and recycling long-lived proteins and organelles, plays a pivotal role in a number of disease states, including cardiovascular diseases [26]. Though the exact mechanisms of mitophagy are far from resolved, it is generally believed that too much mitophagy results in cardiomyocyte death and can contribute to cardiac dysfunction [27] while too little may impair the removal of damaged mitochondria, causing the accumulation of damaged mitochondria which lose mitochondrial membrane potential, produce excess reactive oxygen species, and impart cellular damage [28]. Microtubule associated protein light chain 3 (LC3) is often used as a marker of autophagy; LC3-I (the cytosolic isoform) is converted to LC3-II during the formation of autophagosomes. Additional mitochondrial specific regulators of this process include PINK1 and Parkin [28]. In addition to these protein markers of mitophagy, the process can also be visualized by electron microscopy (EM).

In addition to dynamically undergoing fission and fusion to regulate the mitochondrial network, mitochondrial turnover or biogenesis, creates new mitochondria. Mitochondria have their own DNA (mtDNA) and genetic code that is distinct from nuclear genetics. The biogenesis of mitochondria is a cooperative effort between mitochondrial and nuclear-encoded genes to synthesize all proteins which comprise the five electron transport chain complexes. Biogenesis is transcriptionally regulated by peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC-1α), the "master regulator" of biogenesis [29], transcription factor of mitochondria (TFAM), and nuclear respiratory factor 1 (NRF1) [30]. Biogenesis of mitochondria also requires the synthesis of cardiolipin, a mitochondrial-specific phospholipid located on the inner mitochondrial membrane which regulates respiratory enzyme super complex assembly [31]. The transcriptional assessments of TFAM, PGC-1α and NRF1 or markers of mitochondrial content are often used as surrogates of biogenesis, a cumulative process which is truly represented by net synthesis of mitochondrial proteins and/or lipids into functioning organelles [32].

*2.2.2. Mitochondrial content, dynamics, and function*

6 Mitochondrial Diseases

provide reducing equivalents (NADH and FADH<sup>2</sup>

proteins has profound impact on cardiac function.

The heart is an extremely energetically active organ. Despite accounting for less than 1% of body weight, it consumes roughly 8% of total ATP [4]. The process of energy production and consumption is incredibly dynamic, as the heart only stores enough energy to supply a few beats and turns over the entire metabolite pool every 10 seconds [17]. To meet this costly energy demand, the heart is the most mitochondrially-dense tissue, with mitochondria comprising 25–30% of cardiac myocyte cell volume [18]. Mitochondria are responsible for the majority of ATP production in the healthy heart, with some estimates suggesting that close to 95% of cardiac ATP production occurs through mitochondrial oxidative phosphorylation [19]. Mitochondria are double membrane-bound organelles which are tightly regulated within the myocardium to facilitate efficient energy production. ATP is produced through oxidation of metabolic fuel to

ton motive force across the inner mitochondrial membrane to drive ATP synthesis. Successive electron transfer through complexes I through IV of the electron transport chain culminates in

It has been recognized for quite some time that mitochondria exist in a dynamic reticulum and not as isolate organelles [20]. This network not only allows for efficient ATP production, but also facilitates mitochondrial quality control. The maintenance of this network occurs through continuous mitochondrial fusion and fission, a process mediated by both inner and outer mitochondrial membrane proteins. Fusion, the elongation of the mitochondrial network, increases mitochondrial mass and is regulated mainly by mitofusin-1 and mitofusin-2 (Mfn1 and Mfn2) of the outer mitochondrial membrane and optic atrophy-1 (Opa1) of the inner membrane. Fission, the fragmentation of the mitochondrial network, results in a greater number of smaller mitochondria, and is mediated in part by dynamin-related protein-1 (DRP-1) and fission protein 1 homolog (Fis1) [21]. Fusion and fission are critically necessary for cardiac development as loss of any of these proteins is embryonically lethal [22–24]. Substantial evidence suggests they are also important in the adult heart, as genetic manipulation of these

In addition to regulating mitochondrial shape and size, mitochondrial fission and fusion proteins also regulate mitochondrial quality control through mediating mitophagy, the cellular process of removing damaged mitochondria through autophagy [25]. Autophagy, a highly conserved lysosomal-dependent process of removing damaged cargo and recycling long-lived proteins and organelles, plays a pivotal role in a number of disease states, including cardiovascular diseases [26]. Though the exact mechanisms of mitophagy are far from resolved, it is generally believed that too much mitophagy results in cardiomyocyte death and can contribute to cardiac dysfunction [27] while too little may impair the removal of damaged mitochondria, causing the accumulation of damaged mitochondria which lose mitochondrial membrane potential, produce excess reactive oxygen species, and impart cellular damage [28]. Microtubule associated protein light chain 3 (LC3) is often used as a marker of autophagy; LC3-I (the cytosolic isoform) is converted to LC3-II during the formation of autophagosomes. Additional mitochondrial specific regulators of this process include PINK1 and Parkin [28]. In addition to these protein mark-

ers of mitophagy, the process can also be visualized by electron microscopy (EM).

ATP synthesis through complex V (ATP Synthase) in an oxygen-dependent manner.

) that are coordinately used to generate a pro-

Mitochondrial biology and physiology are further complicated when we consider the arrangement of mitochondrial populations within the adult heart. Three distinct cardiac populations have been identified: the subsarcolemmal mitochondria (SSM), located along the perimeter of the cell, interfibrillar mitochondria (IFM), located between the myofibrils [33], and perinuclear mitochondria which are arranged in clusters surrounding nuclei and are presumably involved with transcriptional activity. Although never directly tested, SSM are hypothesized to provide ATP for basic cell functions, whereas IFM provide energy for the contractile apparatus. The original description of IFM and SSM populations identified differences in biochemical and respiratory properties, as well as ultrastructural differences [33]. Following years of debate as to whether these two populations were different and discrepancy over the causal role of isolation procedures in obscuring differences, consensus seems to have been reached regarding important physiological differences in IFM and SSM. It should be noted that these differences have only been identified in LV mitochondria, and to our knowledge, subpopulations of SSM and IFM have never been described in the RV.

Indeed, most of what we know about mitochondrial structure and function in the healthy heart derives from studies of the LV, and only a few studies have compared healthy right and left ventricles. However, a small report suggests differential expression of autophagy and mitophagy regulators in the RV compared to LV [34]. A proteomic analysis of healthy rabbit and porcine LV and RV free walls demonstrated similar cellular aerobic capacity, mitochondrial volume, mitochondrial electron transport chain content (complexes I, III, IV, and V), as well as mitochondrial enzyme activity [35]. Our group assessed mitochondrial content and electron transport chain activity, as well as protein markers of mitochondrial dynamics in the RV and LV from healthy 2-week old cows (**Figure 1**). While we generally found similar mitochondrial profiles between the ventricles, there were some subtle differences including higher relative copy number of COXI (mt/nDNA) and higher expression of Mfn1 in the RV compared to the LV. Together, the few published papers comparing the LV and RV and the data from our group suggest that though small or subtle, differences exist in mitochondrial physiology in the RV and LV, consistent with the different energetic and functional capacities of the ventricles. A more careful description of interventricular differences will aid in understanding pathological adaptations that occur within these organelles, and the contribution they play in development of cardiac disease.

In addition to damaging macromolecules, excess ROS can trigger apoptosis. The observation that mitochondria trigger cardiomyocyte apoptosis was first described in 1999 [40]. This study demonstrated that when cardiomyocytes are exposed to hydrogen peroxide, Bad, a pro-apoptotic family member of Bcl-2 family, translocates to the mitochondria, resulting in the release of cytochrome c into cytoplasm which leads to the activation of caspase 3 and programmed cell death. Furthermore, both pro-apoptotic proteins Bax and Bak co-localize with Mfn2 on the outer mitochondrial membrane [41]. Drp1 is also recruited by Bax in response to apoptotic stimuli, and colocalizes with Bax at the outer mitochondrial membrane [41]. Conversely, OPA1 is strongly anti-apoptotic by preventing cytochrome c release independent from modulation of fusion [42]. Taken together, these findings suggest that in addition to their roles as primary energy producers, the mitochondria are key contributors to redox homeostasis and regulation of programmed

Mitochondria and Metabolism in Right Heart Failure http://dx.doi.org/10.5772/intechopen.70450 9

While little is known regarding basal differences in ROS production, antioxidant defenses, and apoptotic signaling between the healthy LV and RV, two recent studies suggest differences may exist between the ventricles in healthy hearts and in response to cardiac stress. Schreckenberg and colleagues [43] used a model of systemic nitric oxide (NO) depletion in rats by administration of the pharmacological nitric oxide synthase inhibitor L-NAME. They evaluated cardiac antioxidant capacity in response to L-NAME and in a control (untreated) group. Chronic NO deficiency is associated with oxidant stress, however it appears to do so in a ventricle-specific manner. Dihydroethidium staining, used to detect ROS, showed elevated free radical load in untreated RV control samples compared with the LV, as well as elevated peroxynitrite, both of which were further increased during L-NAME treatment. To identify mechanisms underlying the differential formation of ROS in the LV and RV, the authors examined expression of antioxidant enzymes and found that L-NAME treatment induced SOD2 expression in the LV by 51%, but depressed SOD2 by 30% in the RV. The authors concluded that while the LV increases SOD2 to compensate for increased oxidant load with NO deficiency, the RV does not. Importantly, these biochemical differences in redox status were correlated with changes in RV geometry and function indicative of cardiac dysfunction. A second small study of ischemia–reperfusion injury in a bi-ventricular isolated working heart preparation suggests that mechanisms of myocardial apoptosis also differ between the ventricles. While both ventricles saw similar upregulation of apoptosis in response to ischemia as assessed by cleaved caspase-3 expression, the RV downregulated anti-apoptotic regulator Bcl, while the LV did not [34]. Though this study was small, and performed no follow-up of additional apoptotic regulators or ROS signaling in the healthy heart, it does suggest that different mechanisms may underlie the ability of the two ventricles to regulate ROS production, antioxidant defenses, and apoptosis. Together, this work suggests that inherent differences between the ventricles with respect to these signaling pathways may be especially relevant in response to stresses which promote redox dys-homeostasis including ischemia, reperfusion, and hypoxia.

In response to pathological stress, the heart remodels, resulting in changes in structure, shape, or physiology of the heart and its cellular components. While remodeling can occur

cell death, both of which contribute to healthy and pathological cardiac function.

**3. Cardiac remodeling and heart failure**

**Figure 1.** Mitochondrial content, dynamics, and activity in healthy right ventricle (RV) and left ventricle (LV) from neonatal cows. (A) Representative electron micrographs of the mid-RV and LV of control cows. (B) Expression of electron transport chain complexes does not differ in the healthy ventricles. OXPHOS complex expression was assessed by immunoblotting using an antibody against one subunit of each complex. (C) Representative image. (D) Mitochondrial content, as assessed by mt/nDNA copy number, is slightly different between ventricles, as COX1 copy number is higher in the RV than the LV. (E) Mitofusin-1 (Mfn1) expression is significantly higher in the RV than the LV, with no differences in other mitochondrial dynamics markers. (F) Complex I and V activity do not differ between healthy RV and LV, as assessed by spectrophotometric assay. All comparisons were assessed by Student's t-test. \*p < 0.05, n = 10 in each ventricle. White bars: RV; black bars: LV. Adapted from Bruns, DR et al. AJP-lung, 2014.

#### *2.2.3. Non-energy producing roles for mitochondria in the healthy heart*

Mitochondria are a major source of cardiac reactive oxygen species (ROS), and the largest producer of ROS within the cell [36]. Several labs have identified superoxide (O<sup>2</sup> •−) as the primary mitochondrial source of ROS. Superoxide formation occurs on the outer mitochondrial membrane, in the matrix, and on both sides of the inner membrane. The relative contribution of each site to total O<sup>2</sup> •− varies from tissue to tissue and depends on respiration state of the mitochondria. In heart mitochondria, complex III appears to be most responsible for O<sup>2</sup> •− formation [37]. When mitochondria are functioning normally, ROS production is low. Although a physiological amount of ROS are produced for oxidant-sensitive cell signaling, these ROS are balanced by both mitochondrial and cytosolic scavenging systems to prevent oxidative damage. The matrix contains a specific form of superoxide dismutase (SOD) with manganese in the active site (MnSOD, or SOD2) [38]. SOD2 dismutates O<sup>2</sup> •− into hydrogen peroxide (H2 O2 ), which is catalyzed to water and molecular oxygen by catalase, a major detoxifying enzyme present in heart mitochondria [39]. In addition to these enzymes, other enzymes including glutathione peroxidases, as well as non-enzymatic molecules like vitamins C and E, help to attenuate excess ROS production. However, if ROS production exceeds the ability to remove them, oxidant damage occurs in the form of lipid peroxidation (including oxidation of both inner and outer membranes, and cardiolipin), mitochondrial protein oxidation, and oxidant damage to mtDNA.

In addition to damaging macromolecules, excess ROS can trigger apoptosis. The observation that mitochondria trigger cardiomyocyte apoptosis was first described in 1999 [40]. This study demonstrated that when cardiomyocytes are exposed to hydrogen peroxide, Bad, a pro-apoptotic family member of Bcl-2 family, translocates to the mitochondria, resulting in the release of cytochrome c into cytoplasm which leads to the activation of caspase 3 and programmed cell death. Furthermore, both pro-apoptotic proteins Bax and Bak co-localize with Mfn2 on the outer mitochondrial membrane [41]. Drp1 is also recruited by Bax in response to apoptotic stimuli, and colocalizes with Bax at the outer mitochondrial membrane [41]. Conversely, OPA1 is strongly anti-apoptotic by preventing cytochrome c release independent from modulation of fusion [42]. Taken together, these findings suggest that in addition to their roles as primary energy producers, the mitochondria are key contributors to redox homeostasis and regulation of programmed cell death, both of which contribute to healthy and pathological cardiac function.

While little is known regarding basal differences in ROS production, antioxidant defenses, and apoptotic signaling between the healthy LV and RV, two recent studies suggest differences may exist between the ventricles in healthy hearts and in response to cardiac stress. Schreckenberg and colleagues [43] used a model of systemic nitric oxide (NO) depletion in rats by administration of the pharmacological nitric oxide synthase inhibitor L-NAME. They evaluated cardiac antioxidant capacity in response to L-NAME and in a control (untreated) group. Chronic NO deficiency is associated with oxidant stress, however it appears to do so in a ventricle-specific manner. Dihydroethidium staining, used to detect ROS, showed elevated free radical load in untreated RV control samples compared with the LV, as well as elevated peroxynitrite, both of which were further increased during L-NAME treatment. To identify mechanisms underlying the differential formation of ROS in the LV and RV, the authors examined expression of antioxidant enzymes and found that L-NAME treatment induced SOD2 expression in the LV by 51%, but depressed SOD2 by 30% in the RV. The authors concluded that while the LV increases SOD2 to compensate for increased oxidant load with NO deficiency, the RV does not. Importantly, these biochemical differences in redox status were correlated with changes in RV geometry and function indicative of cardiac dysfunction. A second small study of ischemia–reperfusion injury in a bi-ventricular isolated working heart preparation suggests that mechanisms of myocardial apoptosis also differ between the ventricles. While both ventricles saw similar upregulation of apoptosis in response to ischemia as assessed by cleaved caspase-3 expression, the RV downregulated anti-apoptotic regulator Bcl, while the LV did not [34]. Though this study was small, and performed no follow-up of additional apoptotic regulators or ROS signaling in the healthy heart, it does suggest that different mechanisms may underlie the ability of the two ventricles to regulate ROS production, antioxidant defenses, and apoptosis. Together, this work suggests that inherent differences between the ventricles with respect to these signaling pathways may be especially relevant in response to stresses which promote redox dys-homeostasis including ischemia, reperfusion, and hypoxia.
