M. Faadiel Essop

Hypoxia-induced switches of myosin heavy chain iso-gene expression in rat heart

Cardiac hypertrophy and atrophy increase expression of fetal iso-genes. A common factor is a decrease in cellular oxygen tension. To test the hypothesis that hypoxia changes cardiac MHC iso-gene expression Wistar rats were exposed to 24 and 48 h of hypobaric hypoxia (11% oxygen) and mRNA was isolated from the left ventricle. In addition, neonatal rat cardiomyocytes were incubated for up to 48 h in a hypoxic chamber. Transcript levels of MHCalpha (adult isoform), MHCbeta (fetal isoform), and Nkx2.5, the earliest known marker for cardiogenesis, were measured by real-time quantitative RT-PCR and normalized to levels of 18S rRNA. Expression of the transcription factor Nkx2.5 increased with hypoxia. Hypoxia decreased MHCalpha and increased MHCbeta transcript levels, both in vivo and in vitro. We conclude that hypoxia per se induces a pattern of isoform gene expression associated with early cardiac development.

Acclimatization to chronic hypobaric hypoxia is associated with a differential transcriptional profile between the right and left ventricle

Acute hypobaric hypoxia induces a transient reactivation of the fetal-metabolic gene program in the rat heart. Although chronic hypobaric hypoxia causes alterations in metabolism and cardiac function, little is known about the transcriptional profile associated with acclimatization to chronic hypoxia. Because in chronic hypoxia only the right ventricle is exposed to pressure overload (pulmonary hypertension), we hypothesized that chronic hypobaric hypoxia induces a differential transcriptional profile in the right and left ventricle. Male Wistar rats were exposed to a hypobaric environment (11% O2) for 4, 10, and 12 weeks. Right and left ventricular tissue was isolated for histology and candidate gene expression. Chronic hypobaric hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle, changes in metabolic gene expression suggested a downregulation of fatty acid metabolism and an increase in glucose metabolism, while left ventricular metabolic gene expression suggested restoration of fatty acid metabolism. While myosin heavy chain isoform transcript levels in the right ventricle indicated a progressive reactivation of the fetal iso-gene pattern, there was normalization of myosin iso-gene expression in the left ventricle. Similarly, sarcoendoplasmic reticulum ATPase 2a (SERCA2a) transcript levels in the right ventricle decreased by 12 weeks of chronic hypoxia exposure, whereas, left ventricular SERCA2a expression was unchanged. In conclusion, acclimatization to chronic hypobaric hypoxia induced a differential transcriptional response between the right and left ventricle. We speculate that reactivation of the fetal-metabolic program in the right ventricle is adaptive to pressure overload. (Mol Cell Biochem 278: 71–78, 2005)

A Molecular Phylogeny of Some Bovidae Based on Restriction-Site Mapping of Mitochondrial DNA

Restriction-endonuclease site maps of mitochondrial DNA were constructed for members of the family Bovidae emphasizing species in the Alcelaphinae, Bovinae, and Aepycerotinae. Cladograms weakly supported sister status of the impala, Aepyceros melampus , relative to the Alcelaphinae, and monophyletic status of the Bovini and Tragelaphini. Four members of the Tragelaphini remained an unresolved quadrichotomy, which would be consistent with the inclusion of the eland, Taurotragus oryx , within Tragelaphus . The restriction data are consistent with a radiation for the Tragelaphini at the end of the Miocene.

Metabolic gene switching in the murine female heart parallels enhanced mitochondrial respiratory function in response to oxidative stress

The mechanisms underlying increased cardioprotection in younger female mice are unclear. We hypothesized that serine‐threonine protein kinase (protein kinase B; Akt) triggers a metabolic gene switch (decreased fatty acids, increased glucose) in female hearts to enhance mitochondrial bioenergetic capacity, conferring protection against oxidative stress. Here, we employed male and female control (db/+) and obese (db/db) mice. We found diminished transcript levels of peroxisome proliferator‐activated receptor‐alpha, muscle‐type carnitine palmitoyltransferase 1 and pyruvate dehydrogenase kinase 4 in female control hearts versus male hearts. Moreover, females displayed improved recovery of cardiac mitochondrial respiratory function and higher ATP levels versus males in response to acute oxygen deprivation. All these changes were reversed in female db/db hearts. However, we found no significant gender‐based differences in levels of Akt, suggesting that Akt‐independent signaling mechanisms are responsible for the resilient mitochondrial phenotype observed in female mouse hearts. As glucose is a more energetically efficient fuel substrate when oxygen is limiting, this gene program may be a crucial component that enhances tolerance to oxygen deprivation in female hearts.

Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic (db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MVo₂(unloaded)) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MVo₂(unloaded), because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MVo₂. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MVo₂ following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF + GW-610742 increased FA oxidation to the same extent, only HF increased MVo₂(unloaded). Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MVo₂(unloaded). Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating FAs leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MVo₂ following acute and chronic FA load.

Counter-regulatory effects of incremental hypoxia on the transcription of a cardiac fatty acid oxidation enzyme-encoding gene

Cardiac fatty acid oxidation (FAO) enzyme gene expression is known to be downregulated during hypoxia in concordance with reduced FAO rates. To evaluate this metabolic switch, the transcriptional control of a cardiac FAO enzyme-encoding gene (medium-chain acyl-CoA dehydrogenase, MCAD) was characterized in response to hypobaric hypoxia. Transgenic mice harboring 560-bp of the human MCAD gene promoter fused to the bacterial chloramphenicol acetyl transferase (CAT) reporter gene were exposed to moderate (14% O2) or severe (8% O2) hypoxia for 2 or 7 days. MCAD-CAT activity and gene expression were significantly downregulated following 7 days of moderate hypoxia versus normoxic controls (p < 0.05). In parallel two known transcriptional regulators of MCAD expression, PPARα and Sp3, were concordantly downregulated at 7 days hypoxia. In contrast, severe hypoxia increased MCAD-CAT activity by 31 ± 1.4% after 2 days hypoxia, returning to baseline at 7 days. Endogenous mouse MCAD mRNA expression paralleled this regulation. PPARα steady-state levels were increased (92 ± 9.7%) after 2 days of severe hypoxia (p < 0.01) and remained elevated after 7 days. Sp3 levels increased by 33.4 ± 4% after 2 days (p < 0.001) and returned to control levels after 7 days of hypoxia. These data demonstrate that MCAD gene expression is downregulated after 7 days of moderate hypoxia and inversely regulated with severe hypoxia. The known MCAD transcriptional regulators PPARα and Sp3 mirror MCAD expression. These data indicate that the transcriptional regulatory circuits involved in the control of MCAD gene expression under hypoxic conditions are modulated by upstream factors that are sensitive to the levels of oxygen.

Does Junk Food Lead to Heart Failure? Importance of Dietary Macronutrient Composition in Hypertension

Experimental and clinic studies show that chronic hypertension leads to myocardial pathology and systolic and diastolic dysfunctions that frequently progress to heart failure.1 Elevated afterload causes cardiomyocyte hypertrophy, which alters myocardial energy metabolism by increasing glucose metabolism and impairing mitochondrial oxidative capacity, increasing the production of reactive oxygen species and oxidative damage, and triggering remodeling of the myocardial extracellular matrix and the left ventricle (see Figure).2 Obesity is also a strong risk factor for both hypertension and heart failure and has been increasing at epidemic proportions worldwide.3,4 The increase in obesity in Western societies over the last century is associated with greater consumption of highly processed carbohydrates (eg, sugar, white flour, and white potatoes) and saturated fats.5 At present, there is little information regarding the effects of dietary fat and carbohydrate composition on cardiac function and the development of heart failure in hypertension. Figure. Schematic depiction of the potential impact of a junk-food diet on the development of cardiac pathology essential hypertension. A diet high in sugar, high-glycemic starch, and saturated fats promotes myocardial dysfunction through hypertension and obesity-dependent and -independent pathways. ROS indicates reactive oxygen species. In the present issue of Hypertension , Majane et al6 present the novel finding that consuming a diet that is high in sugar and saturated fat results in relative modest obesity (≈10% increase in body mass) compared with a sugar-free, low-fat diet but greatly accelerates left ventricular dysfunction in a …

Resveratrol co-treatment attenuates the effects of HIV protease inhibitors on rat body weight and enhances cardiac mitochondrial respiration

Since the early 1990s human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV), aspirin (ASP) or vitamin C (VitC) co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides), echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.