Abstract 082: Deletion of Mitochondrial Aldehyde Dehydrogenase 2 Restrains Cardiac Fatty Acid Oxidation during Pressure-Overload Induced Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Aijun Sun ◽  
Guang Xia ◽  
Yunzeng Zou ◽  
Kai Hu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Aldehyde Dehydrogenase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Base Line ◽  
Aldehyde Dehydrogenase 2 ◽  
Metabolic Remodeling

Rationale: Mitochondrial Aldehyde dehydrogenase 2 (ALDH2) is regarded as an inner protector of cardiac diseases, which downregulation has been reported to induce cardiac metabolic remodeling and augmented glucose uptake. However, it has not been investigated whether myocardial fatty acid oxidation (FAO) could be regulated by ALDH2. Objective: We hypothesized that global deletion of ALDH2 would deteriorate heart function and energy generation, inhibit cardiac FAO and promote the development of pressure-overload induced heart failure. Methods and Results: ALDH2 knockout (ALDH2-/-) did not led to considerable birth defects and cardiac dysfunction in base line. Pressure overload were induced by transverse aortic constriction (TAC) for 4weeks. In echocardiographic and hemodynamic test, left ventricular systolic functions were decreased in ALDH2-/- TAC mice compared with wild type (WT) TAC mice. Myocardial morphology and subcellular structure examinations shown ALDH2-/- TAC mice exhibited cardiac hypertrophy with a significant mitochondrial destroy relative to WT-TAC. Meanwhile, a decreased FAO and ATP production were detected (54±3.6% and 77±1.5%, p<0.05,respectively) in ALDH2-/- sham myocardium, which were aggravated by pressure overload. Therefore, ALDH2 deletion accelerated cardiac energy remolding. Furthermore, ALDH2-/- repressed AMP-activated protein kinase (AMPK) phosphorylation(49±4.6%, p<0.05) and subsequently inhibited the activation of peroxisome proliferator-activated receptor a (PPARa) (31±2.9%, p<0.05) - carnitine palmitoyl transferase 1 (CPT1) (81.5±5.2%, p<0.05) - fatty acid transportation pathway, which induced inefficient of FAO. Conclusions: These data of present study suggest that ALDH2 deficiency promotes heart failure and cardiac metabolic remodeling by inhibiting myocardial FAO through AMPK-PPARa-CPT1 pathway.

scholarly journals Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure

2017 ◽  
Vol 312 (2) ◽  
pp. H305-H313 ◽  
Author(s):  
Satoshi Kaimoto ◽  
Atsushi Hoshino ◽  
Makoto Ariyoshi ◽  
Yoshifumi Okawa ◽  
Shuhei Tateishi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Therapeutic Strategy ◽  
Myocardial Function ◽  
Early Stage ◽  
Pressure Overload ◽  
High Energy ◽  
Left Ventricular ◽  
Acid Oxidation

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure. NEW & NOTEWORTHY The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.

Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure

2002 ◽  
Vol 8 (6) ◽  
pp. 416-422 ◽  
Author(s):  
Hani N. Sabbah ◽  
Margaret P. Chandler ◽  
Takayuki Mishima ◽  
George Suzuki ◽  
Pervaiz Chaudhry ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Chronic Heart Failure ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Fatty Acid Oxidation ◽  
Left Ventricular ◽  
Acid Oxidation

57 THE EFFECTS OF INCREASED EXPRESSION OF FATTY ACID OXIDATION ENZYMES ON LEFT VENTRICULAR MASS AND FUNCTION IN HEART FAILURE:

2005 ◽  
Vol 53 (2) ◽  
pp. S366.3-S366
Author(s):  
E. E. Morgan ◽  
T. A. McElfresh ◽  
M. P. Chandler ◽  
M. E. Young ◽  
W. C. Stanley ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Left Ventricular Mass ◽  
Fatty Acid Oxidation ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Ventricular Mass ◽  
And Function

Ranolazine, partial fatty acid oxidation inhibitor improves left ventricular function in dogs with heart failure

2002 ◽  
Vol 34 (6) ◽  
pp. A81
Author(s):  
Margaret P. Chandler ◽  
William C. Stanley ◽  
Hideaki Morita ◽  
George Suzuki ◽  
Omar Nass ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Fatty Acid Oxidation ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Oxidation Inhibitor

Abstract 19826: Cardiac DGAT1 Deficiency Decreases Triglyceride Turnover and Alters Substrate Utilization

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nathan Roe ◽  
Rong Tian
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Contractile Function ◽  
High Energy ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Exogenous Fatty Acid ◽  
Metabolic Remodeling ◽  
Perfused Hearts

Triglyceride (TG) metabolism in the heart has been suggested to regulate PPARα activity and fatty acid oxidation. Reduced TG content and turnover has also been shown in rodent models of heart failure. We found that patients with heart failure displayed decreased mRNA levels of diacylglycerol:acyltransferase 1 (DGAT1), the rate limiting enzyme in TG synthesis (0.56±0.06 fold of NF, p=0.0001) and a lower myocardial TG content (3.65±0.41 vs. 8.27±1.48 mg/g tissue in NF, n=8-11, p=0.019). Therefore we hypothesized reduced TG synthesis caused metabolic remodeling in heart failure. In mice with tamoxifen-inducible cardiac specific deletion of DGAT1 (iKO) TG turnover was reduced. 13 C NMR spectroscopy in perfused hearts revealed a 30% reduction in incorporation of labeled fatty acids (FA) into TG in iKO (40 minute peak area 7.86±0.26 vs. 5.73±0.50) with no changes in total TG content. To test whether these changes affect myocardial energetics and contractile function, we simultaneously measured high energy phosphate content and contractile function using 31 P NMR in isolated perfused hearts. Contractile function and PCr/ATP ratio was unchanged in iKO hearts perfused with FA, lactate and glucose. Furthermore, there is no difference between genotypes in the expression of PPARα or its downstream target genes at baseline or after 5 weeks of high fat diet, indicating that TG turnover has minimal effect on PPARα activity. However, iKO hearts showed increased oxidation of exogenous fatty acid (67.0±4.1% vs. 48.5±5.3%) and reduced glucose oxidation (12.9±4.2% vs. 27.4±4.5%, n=5-7). These observations suggest that reduced TG synthesis diverts exogenous FA from the TG pool towards oxidative metabolism. To evaluate the dependence of iKO hearts upon exogenous FA, hearts were perfused with glucose as the only substrate. The ability to utilize TG was reduced in iKO resulting in a 50% higher TG content after 20 min perfusion, which was associated with a reduced left ventricular developed pressure (119±6 vs. 97±7 mmHg for control and iKO respectively). Taken together, we found that DGAT1 deficiency in the heart reduced TG turnover and increased reliance on the oxidation of exogenous FA, a phenotype that may contribute to the lack of metabolic flexibility in heart failure.

scholarly journals Progesterone receptor membrane component 1 reduces cardiac steatosis and lipotoxicity via activation of fatty acid oxidation and mitochondrial respiration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sang R. Lee ◽  
Jun H. Heo ◽  
Seong Lae Jo ◽  
Globinna Kim ◽  
Su Jung Kim ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Progesterone Receptor ◽  
Fatty Acid Oxidation ◽  
Mitochondrial Respiration ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Membrane Component ◽  
Markers Of Inflammation ◽  
Receptor Membrane

AbstractObesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure.

scholarly journals Modulating fatty acid oxidation in heart failure

2011 ◽  
Vol 90 (2) ◽  
pp. 202-209 ◽  
Author(s):  
V. Lionetti ◽  
W. C. Stanley ◽  
F. A. Recchia
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation
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