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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 Angiotension II (Ang II)-treated cardiomyocytes and in hearts of Ang II-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 deacetylates 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 mitochondria NAD. Taken together, these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Background and aims It is commonly believed that diabetes is an important contributor to heart failure (HF) development. However, the detail effect of diabetogenesis on HF is controversy: both beneficial and harmful roles were reported. In the present study, we aim to explore the unambiguous action of diabetes on chronic HF progression and the underlying mechanism. Methods Diabetes and myocardial infarction (MI) were induced by streptozotocin (STZ) injection and left-sided thoracotomy and left anterior descending coronary artery (LAD) ligation, respectively. Pyridoxamine was used as the antagonist of advanced glycation end products (AGEs). Adult male SD rats were assigned to 5 groups: Sham; MI; Diabetes (D); Diabetes + MI (DMI) and DMI + pyridoxamine (DMI + P). Animals were sacrificed at the end of 12 weeks. The comparison of LV myocardium was made between border zone from MI or DMI animals and control LV tissues from sham-operated animals. Cardiomyocytes and dendritic cells were prepared from the Sprague–Dawley rats and cocultured in the presence or absence of AGEs. Results DMI group showed highest level of AGEs and inflammatory markers, which were significantly reduced in the presence of pyridoxamine. In vitro experiment disclosed AGEs could stimulate DCs differentiation and promote cytokines production, finally upregulated hypertrophy-related genes expression in cardiocytes. Intervention DCs differentiation was sufficient to improve cardiocytes morphology. Conclusion Our results clearly demonstrate that diabetes would promote chronic HF progression at least in part through stimulating DCs differentiation and series downstream inflammatory responses induced by AGEs. [ABSTRACT FROM AUTHOR]

Highlights: [•] Elevated NF-κB activity in neonatal rat cardiomyocytes overexpressing RIP140. [•] RIP140 impacts proinflammatory response of cardiomyocytes via p65-NF-κB pathway. [•] p65-NF-κB is involved in RIP140-induced metabolic dysregulation in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Highlights: [•] Salvianolic acid B (SalB) protected cardiomyocytes from AngII-induced hypertrophy. [•] SalB’ anti-hypertrophy was partly attributed to its inhibition on PARP-1. [•] SalB prevented the depletion of cellular NAD+ induced by AngII. [•] SalB’s antioxidant effect might contribute to the inhibition of PARP-1. [ABSTRACT FROM AUTHOR]

Abstract: Growing evidences have shown that hypertension, cardiac hypertrophy and fibrosis were associated with an overactivity of NAD(P)H oxidase. It is unknown, however, which isoform of NAD(P)H oxidase yields O2 − formation in heart and aorta in two-kidney, two-clip (2K2C) hypertensive rats in vivo and thus is responsible for the development of cardiac remodeling. We examined the pathological change of NAD(P)H oxidase homologues and tested the effect of valsartan on the cardiac remodeling in 2K2C renovascular hypertensive rats. Four weeks after male Sprague–Dawley rats accepted 2K2C or sham operation, 2K2C hypertensive (>160mmHg) rats were divided into vehicle-treated (2K2C) and valsartan (30mgkg−1 per day, for 6 weeks)-treated (2K2C+Val) groups, which were compared with sham-operated controls (Sham). At week 10, 2K2C hypertensive rats showed increased serum level of angiotensin II (Ang II), MDA and blood pressure (BP), obvious cardiac hypertrophy and fibrosis, increased O2 − production and NAD(P)H oxidase activity and expression in aorta and heart. The heart in 2K2C hypertensive rats preferred to use NADH as substrate while the aorta used both NADH and NADPH. Valsartan treatment decreased BP, ameliorated cardiac hypertrophy and fibrosis, decreased O2 − production and NAD(P)H oxidase activity in aorta and heart. Nox2 and Nox4 protein expression increased in heart, while Nox1 and Nox4 increased in aorta in 2K2C hypertensive rats, which were all normalized after valsartan treatment. In conclusion, these data indicate that different Nox expression might account for substrate preference and the formation of O2 − by NAD(P)H oxidase resulting from elevated Ang II in the 2K2C model contributes to the development of renovascular hypertension and subsequent cardiac remodeling. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptors (PPARα, β/δ and γ) are nuclear receptors and PPARγ activation was previously reported to inhibit collagen expression in the heart, but whether PPARβ/δ also regulates collagen expression in the heart remains unclear. In this study, we investigated the effect of PPARβ/δ activation on angiotensin II (Ang II)-induced collagen type I expression in adult rat cardiac fibroblasts. The results showed that PPARβ/δ was expressed at the moderate level in cardiac fibroblasts. GW501516, a selective PPARβ/δ agonist, depressed Ang II-stimulated collagen type I expression and collagen synthesis in cardiac fibroblasts in a concentration-dependent manner. Furthermore, these inhibitory effects of GW501516 were completely reversed by the knockdown of PPARβ/δ via RNA interference. In summary, we find that PPARβ/δ is present in cardiac fibroblasts and PPARβ/δ activation inhibits Ang II-induced collagen type I expression at least in part via decreasing collagen synthesis. PPARβ/δ may be a promising therapeutic target for myocardial fibrosis. [Copyright &y& Elsevier]

A graphical abstract showing that Cryptotanshinone protected against pulmonary fibrosis through inhibition of both TGF-β/Smad and STAT3 signaling pathways. Cryptotanshinone (CTS), a lipophilic compound extracted from root of Salvia miltiorrhiza (Danshen), has demonstrated multiple pharmacological activities, including anti-inflammation, anti-proliferation and anti-infection. However, the effect of CTS on pulmonary fibrosis is unknown. This study aims to investigate the effects of CTS treatment on pulmonary fibrosis and its underlying mechanism. The pulmonary fibrosis model was established by intratracheal instillation of bleomycin (5 mg/kg) in Sprague-Dawley rats (in vivo) and stimulating human fetal lung fibroblasts (HLFs) with transforming growth factor-beta 1 (TGF-β1) (in vitro). CTS (7.5, 15, 30, 60 mg/kg/day) and pirfenidone (150 mg/kg/day, positive control) were administered by oral gavage for 28 days. In this study, we found CTS treatment improved pulmonary function, relieved pathological changes and attenuated the accumulation of extracellular matrix in pulmonary fibrosis rat model induced by bleomycin. Mechanistically, CTS suppressed phosphorylation of Smad2/3 and STAT3 induced by TGF-β1 in HLFs. Stattic, a 1-benzothiophene based small-molecule STAT3 inhibitor, resulted in a significant down-regulation of fibrosis biomarkers including fibronectin, collagen type I and alpha smooth muscle actin (α-SMA). Overexpression of STAT3 promoted expression of fibrosis biomarkers in HLFs cell model induced by TGF-β1 and partially blocked the inhibitory effect of CTS on TGF-β1-induced fibrosis response. Taken together, these results suggested that CTS protects against pulmonary fibrosis via inhibition of Smad and STAT3 signaling pathways. Thus, CTS may represent a promising drug candidate for treating pulmonary fibrosis. [ABSTRACT FROM AUTHOR]