We conclude that increased cardiac fatty acid oxidation in response to high-fat feeding is controlled, in part, via the down-regulation of SIRT3 and concomitant increased acetylation of mitochondrial β-oxidation enzymes.
Background-The angiotensin-converting enzyme 2 and angiotensin-(1-7) (Ang 1-7)/MasR (Mas receptor) axis are emerging as a key pathway that can modulate the development of diabetic cardiomyopathy. We studied the effects of Ang 1-7 on diabetic cardiomyopathy in db/db diabetic mice to elucidate the therapeutic effects and mechanism of action. Methods and Results-Ang 1-7 was administered to 5-month-old male db/db mice for 28 days via implanted microosmotic pumps. Ang 1-7 treatment ameliorated myocardial hypertrophy and fibrosis with normalization of diastolic dysfunction assessed by pressure-volume loop analysis and echocardiography. The functional improvement by Ang 1-7 was accompanied by a reduction in myocardial lipid accumulation and systemic fat mass and inflammation and increased insulin-stimulated myocardial glucose oxidation. Increased myocardial protein kinase C levels and loss of phosphorylation of extracellular signal-regulated kinase 1/2 were prevented by Ang 1-7. Furthermore, Ang 1-7 treatment decreased cardiac triacylglycerol and ceramide levels in db/db mice, concomitantly with an increase in myocardial adipose triglyceride lipase expression. Changes in adipose triglyceride lipase expression correlated with increased SIRT1 (silent mating type information regulation 2 homolog 1) levels and deacetylation of FOXO1 (forkhead box O1). Conclusions-We identified a novel beneficial effect of Ang 1-7 on diabetic cardiomyopathy that involved a reduction in cardiac hypertrophy and lipotoxicity, adipose inflammation, and an upregulation of adipose triglyceride lipase. Ang 1-7 completely rescued the diastolic dysfunction in the db/db model. Ang 1-7 represents a promising therapy for diabetic cardiomyopathy associated with type 2 diabetes mellitus. (Circ Heart Fail. 2014;7:327-339.)
The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.
(1) Background: There is a growing need for the development of new methods for the synthesis of nanoparticles. The interest in such particles has raised concerns about the environmental safety of their production methods; (2) Objectives: The current methods of nanoparticle production are often expensive and employ chemicals that are potentially harmful to the environment, which calls for the development of “greener” protocols. Herein we describe the synthesis of gold nanoparticles (AuNPs) using plant extracts, which offers an alternative, efficient, inexpensive, and environmentally friendly method to produce well-defined geometries of nanoparticles; (3) Methods: The phytochemicals present in the aqueous leaf extract acted as an effective reducing agent. The generated AuNPs were characterized by Transmission electron microscopy (TEM), Scanning electron microscope (SEM), and Atomic Force microscopy (AFM), X-ray diffraction (XRD), UV-visible spectroscopy, energy dispersive X-ray (EDX), and thermogravimetric analyses (TGA); (4) Results and Conclusions: The prepared nanoparticles were found to be biocompatible and exhibited no antimicrobial or antifungal effect, deeming the particles safe for various applications in nanomedicine. TGA analysis revealed that biomolecules, which were present in the plant extract, capped the nanoparticles and acted as stabilizing agents.
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