Numerous conditions promote oxidative stress, leading to the build-up of reactive aldehydes that cause cell damage and contribute to cardiac diseases. Aldehyde dehydrogenases (ALDHs) are important enzymes that eliminate toxic aldehydes by catalysing their oxidation to non-reactive acids. The review will discuss evidence indicating a role for a specific ALDH enzyme, the mitochondrial ALDH2, in combating oxidative stress by reducing the cellular ‘aldehydic load’. Epidemiological studies in humans carrying an inactive ALDH2, genetic models in mice with altered ALDH2 levels, and small molecule activators of ALDH2 all highlight the role of ALDH2 in cardioprotection and suggest a promising new direction in cardiovascular research and the development of new treatments for cardiovascular diseases.

Heart failure (HF) afflicts about 5 million people and causes 300 000 deaths a year in the United States alone. An integral part of the pathogenesis of HF is cardiac remodelling, and the signalling events that regulate it are a subject of intense research. Cardiac remodelling is the sum of responses of the heart to causes of HF, such as ischaemia, myocardial infarction, volume and pressure overload, infection, inflammation, and mechanical injury. These responses, including cardiomyocyte hypertrophy, myocardial fibrosis, and inflammation, involve numerous cellular and structural changes and ultimately result in a progressive decline in cardiac performance. Pharmacological and genetic manipulation of cultured heart cells and animal models of HF and the analysis of cardiac samples from patients with HF are all used to identify the molecular and cellular mechanisms leading to the disease. Protein kinase C (PKC) isozymes, a family of serine–threonine protein kinase enzymes, were found to regulate a number of cardiac responses, including those associated with HF. In this review, we describe the PKC isozymes that play critical roles in specific aspects of cardiac remodelling and dysfunction in HF.

AimsProtein kinase C epsilon (PKCε) is critical for cardiac protection from ischaemia and reperfusion (IR) injury. PKCε substrates that mediate cytoprotection reside in the mitochondria. However, the mechanism enabling mitochondrial translocation and import of PKCε to enable phosphorylation of these substrates is not known. Heat shock protein 90 (HSP90) is a cytoprotective protein chaperone that participates in mitochondrial import of a number of proteins. Here, we investigated the role of HSP90 in mitochondrial import of PKCε.Methods and resultsUsing an ex vivo perfused rat heart model of IR, we found that PKCε translocates from the cytosol to the mitochondrial fraction following IR. Immunogold electron microscopy and mitochondrial fractionation demonstrated that following IR, mitochondrial PKCε is localized within the mitochondria, on the inner mitochondrial membrane. Pharmacological inhibition of HSP90 prevented IR-induced interaction between PKCε and the translocase of the outer membrane (Tom20), reduced mitochondrial import of PKCε, and increased necrotic cell death by ∼70%. Using a rational approach, we designed a 7-amino acid peptide activator of PKCε, derived from an HSP90 homologous sequence located in the C2 domain of PKCε (termed ψεHSP90). Treatment with this peptide (conjugated to the cell permeating TAT protein-derived peptide, TAT47–57) increased PKCε–HSP90 protein–protein interaction, enhanced mitochondrial translocation of PKCε, increased phosphorylation and activity of an intra-mitochondrial PKCε substrate, aldehyde dehydrogenase 2, and reduced cardiac injury in ex vivo and in vivo models of myocardial infarction.ConclusionOur results suggest that HSP90-mediated mitochondrial import of PKCε plays an important role in the protection of the myocardium from IR injury.

Nitroglycerin, which helps impaired cardiac function as it is converted to nitric oxide, is used worldwide to treat patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance is a result of inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction (MI). Here we tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent MI. In a rat model of MI, 16 hours of prior, sustained nitroglycerin treatment (7.2 mg/kg/day) resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the MI. We also sought to identify a potential treatment to protect against this increased cardiac damage. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 (16 mg/kg/day) with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after MI in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If our animal studies showing that nitroglycerin tolerance increases cardiac injury upon ischemic insult are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect MI patients from this nitroglycerin-induced increase in cardiac injury, while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin.

Abstract-Studies on genetically manipulated mice suggest a role for -protein kinase C (PKC) in cardiac hypertrophy and in heart failure. The potential clinical relevance of these findings was tested here using a pharmacological inhibitor of PKC activity during the progression to heart failure in hypertensive Dahl rats. Dahl rats, fed an 8% high-salt diet from the age of 6 weeks, exhibited compensatory cardiac hypertrophy by 11 weeks, followed by heart failure at Ϸ17 weeks and death by the age of Ϸ20 weeks (123Ϯ3 days). Sustained treatment between weeks 11 and 17 with the selective PKC inhibitor V1-2 or with an angiotensin II receptor blocker olmesartan prolonged animal survival by Ϸ5 weeks (V1-2: 154Ϯ7 days; olmesartan: 149Ϯ5 days). These treatments resulted in improved fractional shortening (V1-2: 58Ϯ2%; olmesartan: 53Ϯ2%; saline: 41Ϯ6%) and decreased cardiac parenchymal fibrosis when measured at 17 weeks without lowering blood pressure at any time during the treatment. Combined treatment with V1-2, together with olmesartan, prolonged animal survival by 5 weeks (37 days) relative to olmesartan alone (from 160Ϯ5 to 197Ϯ14 days, respectively) and by Ϸ11 weeks (74 days) on average relative to saline-treated animals, suggesting that the pathway inhibited by PKC inhibition is not identical to the olmesartan-induced effect. These data suggest that an PKC-selective inhibitor such as V1-2 may have a potential in augmenting current therapeutic strategies for the treatment of heart failure in humans. Key Words: heart failure Ⅲ protein kinase C Ⅲ ventricular remodeling Ⅲ hypertrophy Ⅲ fibrosis A lthough two-thirds of cases of heart failure in the United States are because of myocardial infarction, hypertension is a major contributor to this morbidity. Therefore, we studied hypertension-induced heart failure using hypertensive salt-sensitive Dahl rats. 1,2 Because many of the signaling events associated with heart failure involve activation of protein kinase C (PKC), 1,3 we determined whether PKC regulation affects disease progression. We focused on PKC, because there are conflicting reports on its role in cardiac hypertrophy and heart failure based on genetic manipulation of mice. 1,4 -6 Because the enzyme may have different roles during heart development, we used a pharmacological approach to selectively inhibit it at a defined time during disease.We previously designed isozyme-selective peptide regulators of PKC, which function by inhibiting or activating PKC translocation. These peptide regulators are linked to membrane-permeable peptides, TAT [47][48][49][50][51][52][53][54][55][56][57] , to enable their effective intracellular delivery and are, therefore, useful pharmacological tools. Using the Dahl salt-sensitive hypertension-induced heart failure rat model, 1,2 we determined here whether sustained pharmacological inhibition of PKC with the abovementioned peptide or with an angiotensin receptor blocker, olmesartan, delays progression to heart failure. Methods Hypertension-Induced Heart Failure ModelAnimal protocols ...