ABSTRACT
Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease(OHD),which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism. SIRT3, a mitochondria-localized sirtuin, regulates global mitochondrial lysine acetylation and preserves mitochondrial function. However, the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated. In this study, we firstly demonstrated that expression of SIRT3 was decreased in AngiotensionⅡ(AngⅡ)-treated cardiomyocytes and in hearts of AngⅡ-induced cardiac hypertrophic mice. In addition, SIRT3 overexpression protected myocytes from hypertrophy, whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy.In particular,SIRT3-KO mice exhibited significant cardiac hypertrophy. Mechanistically, we identified NMNAT3 (nicotinamide mononucleotide adenylyltransferase 3), the rate-limiting enzyme for mitochondrial NAD biosynthesis, as a new target and binding partner of SIRT3.Specifically,SIRT3 physically interacts with and deacety-lates NMNAT3,thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects.Moreover,NMNAT3 regulates the activity of SIRT3 via synthesis of mitochon-dria NAD.Taken together,these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.Sirtuin 3(SIRT3),a mitochondrial deacetylase that may play an impor-tant role in regulating cardiac function and a potential target for CHF
ABSTRACT
<p><b>BACKGROUND</b>Berberine is one of the main constituents of Coptidis rhizoma (CR) and Cortex phellodendri. In this study, we investigated the beneficial effects of berberine on renal function and its possible mechanisms in rats with diabetic nephropathy (DN).</p><p><b>METHODS</b>Male Wistar rats were divided into three groups: normal, diabetic model, and berberine treatment groups. Rats in the diabetic model and berberine treatment groups were induced to diabetes by intraperitonal injection with streptozotocin (STZ). Glomerular area, glomerular volume, fasting blood glucose (FBG), blood urea nitrogen (BUN), serum creatinine (Cr) and urine protein for 24 hours (UP24h) were measured using commercially available kits. Meanwhile, the activity of superoxide dismutase (SOD), content of malondialdehyde (MDA) in serum, activity of aldose reductase (AR) and the expression of AR mRNA and protein in kidney were detected by different methods.</p><p><b>RESULTS</b>The results showed that oral administration of berberine (200 mg x kg(-1) x d(-1)) significantly ameliorated the ratio of kidney weight to body weight. Glomerular area, glomerular volume, FBG, BUN, Cr and UP24h were significantly decreased in the berberine treatment group compared with the diabetic model group (P < 0.05). Berberine treatment significantly increased serum SOD activity and decreased the content of MDA compared with diabetic model group (P < 0.05). AR activity as well as the expression of AR mRNA and protein in the kidney was markedly decreased in the berberine treatment group compared with diabetic model group (P < 0.05).</p><p><b>CONCLUSION</b>These results suggested that berberine could ameliorate renal dysfunction in DN rats through controlling blood glucose, reduction of oxidative stress and inhibition of the activation of the polyol pathway.</p>