Lipid Use and Misuse by the Heart Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J
Circulation research,
2016-May-27, Letnik:
118, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that ...affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested.
The heart has both the greatest caloric needs and the most robust oxidation of fatty acids (FAs). Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation are ...not balanced and hearts accumulate lipid potentially leading to cardiac lipotoxicity. We will first review the pathways utilized by the heart to acquire FAs from the circulation and to store triglyceride intracellularly. Then we will describe mouse models in which excess lipid accumulation causes heart dysfunction and experiments performed to alleviate this toxicity. Finally, the known relationships between heart lipid metabolism and dysfunction in humans will be summarized.
Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and ...are synthesized by distinct enzymes, ceramide synthase (CerS)1‐CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5‐derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain‐length de‐ pendent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria‐targeted ceramides led to mitophagy in a manner proportional to N‐acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.—Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very‐long‐chain ceramides cause mito‐ chondrial dysfunction, oxidative stress, and cell death in cardiomyocytes. FASEB J. 32,1403‐1416 (2018). www.fasebj.org
In this study, we aim to gain a better insight on how habitat filtering due to urbanization shapes bird communities of Vienna city parks. This may help to derive implications for urban planning in ...order to promote and maintain high diversity and ecosystem function in an increasing urbanized environment. The structure of wintering bird communities of 36 Vienna city parks – surveyed once a month in January 2009, December 2009, December 2012, and January 2013 – was described by species richness and the functional diversity measurements FRic (functional richness), FEve (functional evenness), and FDiv (functional divergence). Environmental filtering was quantified by park size, canopy heterogeneity within the park, and the proportion of sealed area surrounding each park. Species richness, FRic, and FDiv increased with increasing park size. Sealed area had a strong negative effect on species richness and FDiv. Canopy heterogeneity played a minor role in explaining variance in FDiv data. FEve did not respond to any of these park parameters. Our results suggest a loss of species richness and functional diversity, hence most likely indicate a decline in ecosystem function, with decreasing park size and increasing sealed area of the surrounding urban landscape matrix.
The functional diversity of wintering bird communities in city parks of Vienna was quantified to gain a better insight on how habitat filtering due to urbanisation shapes bird communities. Environmental filtering was quantified by park size, canopy heterogeneity within the park and the proportion of sealed area surrounding each park. Our results suggest a loss of species richness and functional diversity, hence most likely indicate a decline in ecosystem function, with decreasing park size and increasing sealed area of the surrounding urban landscape matrix.
Pentacyclic triterpenes are diverse plant secondary metabolites derived from the mevalonate (MVA) pathway. Many of these molecules are potentially valuable, particularly as pharmaceuticals, and ...research has focused on their production in simpler and more amenable heterologous systems such as the yeast
Saccharomyces cerevisiae
. We have developed a new heterologous platform for the production of pentacyclic triterpenes in
S. cerevisiae
based on a combinatorial engineering strategy involving the overexpression of MVA pathway genes, the knockout of negative regulators, and the suppression of a competing pathway. Accordingly, we overexpressed
S. cerevisiae ERG13
, encoding 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, and a truncated and deregulated variant of the rate-limiting enzyme HMG-CoA reductase 1 (tHMGR). In the same engineering step, we deleted the
ROX1
gene, encoding a negative regulator of the MVA pathway and sterol biosynthesis, resulting in a push-and-pull strategy to enhance metabolic flux through the system. In a second step, we redirected this enhanced metabolic flux from late sterol biosynthesis to the production of 2,3-oxidosqualene, the direct precursor of pentacyclic triterpenes. In yeast cells transformed with a newly isolated sequence encoding lupeol synthase from the Russian dandelion (
Taraxacum koksaghyz
), we increased the yield of pentacyclic triterpenes by 127-fold and detected not only high levels of lupeol but also a second valuable pentacyclic triterpene product, β-amyrin.
Aims
To assess the impact of the lockdown due to coronavirus disease 2019 (COVID-19) on key quality indicators for the treatment of ST-segment elevation myocardial infarction (STEMI) patients.
...Methods
Data were obtained from 41 hospitals participating in the prospective Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) study, including 15,800 patients treated for acute STEMI from January 2017 to the end of March 2020.
Results
There was a 12.6% decrease in the total number of STEMI patients treated at the peak of the pandemic in March 2020 as compared to the mean number treated in the March months of the preceding years. This was accompanied by a significant difference among the modes of admission to hospitals (
p
= 0.017) with a particular decline in intra-hospital infarctions and transfer patients from other hospitals, while the proportion of patients transported by emergency medical service (EMS) remained stable. In EMS-transported patients, predefined quality indicators, such as percentages of pre-hospital ECGs (both 97%, 95% CI = − 2.2–2.7,
p
= 0.846), direct transports from the scene to the catheterization laboratory bypassing the emergency department (68% vs. 66%, 95% CI = − 4.9–7.9,
p
= 0.641), and contact-to-balloon-times of less than or equal to 90 min (58.3% vs. 57.8%, 95%CI = − 6.2–7.2,
p
= 0.879) were not significantly altered during the COVID-19 crisis, as was in-hospital mortality (9.2% vs. 8.5%, 95% CI = − 3.2–4.5,
p
= 0.739).
Conclusions
Clinically important indicators for STEMI management were unaffected at the peak of COVID-19, suggesting that the pre-existing logistic structure in the regional STEMI networks preserved high-quality standards even when challenged by a threatening pandemic.
Clinical trial registration
NCT00794001
Phytosterols and Cardiovascular Disease Makhmudova, Umidakhon; Schulze, P. Christian; Lütjohann, Dieter ...
Current atherosclerosis reports,
11/2021, Letnik:
23, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
Coronary heart disease is the leading cause of mortality worldwide. Elevated blood cholesterol levels are not only the major but also the best modifiable cardiovascular risk factor. ...Lifestyle modifications which include a healthy diet are the cornerstone of lipid-lowering therapy. So-called functional foods supplemented with plant sterols lower blood cholesterol levels by about 10–15%.
Recent Findings
In the recent revision of the ESC/EAS dyslipidemia guideline 2019, plant sterols are recommended for the first time as an adjunct to lifestyle modification to lower blood cholesterol levels. However, the German Cardiac Society (DGK) is more critical of food supplementation with plant sterols and calls for randomized controlled trials investigating hard cardiovascular outcomes. An increasing body of evidence suggests that plant sterols per se are atherogenic.
Summary
This review discusses this controversy based on findings from in vitro and in vivo studies, clinical trials, and genetic evidence.
Abstract Background Hypertrophic cardiomyopathy (HCM) is caused by mutations in different structural genes and induces pathological hypertrophy with sudden cardiac death as a possible consequence. ...HCM can be separated into hypertrophic non-obstructive and obstructive cardiomyopathy (HNCM/HOCM) with different clinical treatment approaches. We here distinguished between HNCM, HOCM, cardiac amyloidosis and aortic stenosis by using microRNA profiling and investigated potential interactions between circulating miRNA levels and the most common mutations in MYH7and MYBPC3 genes. Methods Our study included 4 different groups: 23 patients with HNCM, 28 patients with HOCM, 47 patients with aortic stenosis and 22 healthy controls. Based on previous findings, 8 different cardiovascular known microRNAs (miR-1, miR-21, miR-29a, miR-29b, miR-29c, miR-133a, miR-155 and miR-499) were studied in serum of all patients and compared with clinically available patient data. Results We found miR-29a levels to be increased in patients with HOCM and correlating markers of cardiac hypertrophy. This was not the case in HNCM patients. In contrast, we identified miR-29c to be upregulated in aortic stenosis but not the other patient groups. ROC curve analysis of miR-29a/c distinguished between HOCM patients and aortic stenosis patients. MiR-29a and miR-155 levels discriminated HNCM patients from patients with senile cardiac amyloidosis. MiR-29a increased mainly in HOCM patients with a mutation in MYH7, whereas miR-155 was decreased in hypertrophic cardiomyopathy patients with a mutation in MYBPC3. Conclusion We demonstrated that miR-29a and miR-29c show a specific signature to distinguish between aortic stenosis, hypertrophic non-obstructive and obstructive cardiomyopathies and thus could be developed into clinically useful biomarkers.
Summary
Natural rubber (NR) is an important raw material for a large number of industrial products. The primary source of NR is the rubber tree Hevea brasiliensis, but increased worldwide demand ...means that alternative sustainable sources are urgently required. The Russian dandelion (Taraxacum koksaghyz Rodin) is such an alternative because large amounts of NR are produced in its root system. However, rubber biosynthesis must be improved to develop T. koksaghyz into a commercially feasible crop. In addition to NR, T. koksaghyz also produces large amounts of the reserve carbohydrate inulin, which is stored in parenchymal root cell vacuoles near the phloem, adjacent to apoplastically separated laticifers. In contrast to NR, which accumulates throughout the year even during dormancy, inulin is synthesized during the summer and is degraded from the autumn onwards when root tissues undergo a sink‐to‐source transition. We carried out a comprehensive analysis of inulin and NR metabolism in T. koksaghyz and its close relative T. brevicorniculatum and functionally characterized the key enzyme fructan 1‐exohydrolase (1‐FEH), which catalyses the degradation of inulin to fructose and sucrose. The constitutive overexpression of Tk1‐FEH almost doubled the rubber content in the roots of two dandelion species without any trade‐offs in terms of plant fitness. To our knowledge, this is the first study showing that energy supplied by the reserve carbohydrate inulin can be used to promote the synthesis of NR in dandelions, providing a basis for the breeding of rubber‐enriched varieties for industrial rubber production.
Summary
Laticifers are hypothesized to mediate both plant–herbivore and plant–microbe interactions. However, there is little evidence for this dual function.
We investigated whether the major ...constituent of natural rubber, cis‐1,4‐polyisoprene, a phylogenetically widespread and economically important latex polymer, alters plant resistance and the root microbiome of the Russian dandelion (Taraxacum koksaghyz) under attack of a root herbivore, the larva of the May cockchafer (Melolontha melolontha).
Rubber‐depleted transgenic plants lost more shoot and root biomass upon herbivory than normal rubber content near‐isogenic lines. Melolontha melolontha preferred to feed on artificial diet supplemented with rubber‐depleted rather than normal rubber content latex. Likewise, adding purified cis‐1,4‐polyisoprene in ecologically relevant concentrations to diet deterred larval feeding and reduced larval weight gain. Metagenomics and metabarcoding revealed that abolishing biosynthesis of natural rubber alters the structure but not the diversity of the rhizosphere and root microbiota (ecto‐ and endophytes) and that these changes depended on M. melolontha damage. However, the assumption that rubber reduces microbial colonization or pathogen load is contradicted by four lines of evidence.
Taken together, our data demonstrate that natural rubber biosynthesis reduces herbivory and alters the plant microbiota, which highlights the role of plant‐specialized metabolites and secretory structures in shaping multitrophic interactions.
See also the Commentary on this article by Domeignoz‐Horta & Schuman, 239: 1160–1163.
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