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Huoxue Qianyang Qutan recipe attenuates Ang II-induced cardiomyocyte hypertrophy by regulating reactive oxygen species production

ABSTRACT: Continuous and irreversible cardiac hypertrophy can induce cardiac maladaptation and cardiac remodeling, resulting in increased risk of developing cardiovascular diseases. The present study was conducted to investigate the therapeutic effect of Huoxue Qianyang Qutan recipe (HQQR) on angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from the cardiac tissue of neonatal rats, followed by flow cytometry detection to confirm the proportion of primary cardiomyocytes. Cell Counting Kit-8 assay and immunofluorescence detection were performed to examine the effect of Ang II and HQQR on cardiomyocyte hypertrophy. Reactive oxygen species (ROS) and a series of metabolic indicators were quantified to investigate the effect of HQQR on Ang II-induced cardiomyocyte hypertrophy. Mitochondrial electron transport chain complex activity and related coding gene expression were determined to explore the effect of HQQR on mitochondrial function. HQQR significantly inhibited Ang II-induced cardiomyocyte hypertrophy and restored Ang II-induced ROS accumulation, metabolic indicators, and membrane potential levels. HQQR also regulated the mitochondrial function related to the sirtuin 1 pathway in Ang II-induced cardiomyocytes by increasing the activity of the mitochondrial electron transport chain complex and affecting the expression of genes encoding mitochondrial electron transport chain complex subunits. HQQR could alleviate Ang II-induced cardiomyocyte hypertrophy by modulating oxidative stress, accumulating ROS and increasing mitochondrial electron transport chain activity.

SUBMITTER: Gui M

PROVIDER: S-EPMC8549094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cardiac hypertrophy (CH) is characterized by an increase in cardiomyocyte size, and is the most common cause of cardiac-related sudden death. A decrease in gap junction (GJ) coupling and mitochondrial dysfunction are important features of CH, but the mechanisms of decreased coupling and energy impairment are poorly understood. It has been reported that GJA1-20k has a strong tropism for mitochondria and is required for the trafficking of connexin 43 (Cx43) to cell-cell borders. In this study, we investigated the effects of GJA1-20k on Cx43 GJ coupling and mitochondrial function in the pathogenesis of CH. We performed hematoxylin-eosin (HE) and Masson staining, and observed significant CH in 18-week-old male spontaneously hypertensive rats (SHRs) compared to age-matched normotensive Wistar-Kyoto (WKY) rats. In cardiomyocytes from SHRs, the levels of Cx43 at the intercalated disc (ID) and the expression of GJA1-20k were significantly reduced, whereas JAK-STAT signaling was activated. Furthermore, the SHR rats displayed suppressed mitochondrial GJA1-20k and mitochondrial biogenesis. Administration of valsartan (10 mg· [Formula: see text] d-1, i.g., for 8 weeks) prevented all of these changes. In neonatal rat cardiomyocytes (NRCMs), overexpression of GJA1-20k attenuated Ang II-induced cardiomyocyte hypertrophy and caused elevated levels of GJ coupling at the cell-cell borders. Pretreatment of NRCMs with the Jak2 inhibitor AG490 (10 µM) blocked Ang II-induced reduction in GJA1-20k expression and Cx43 gap junction formation; knockdown of Jak2 in NRCMs significantly lessened Ang II-induced cardiomyocyte hypertrophy and normalized GJA1-20k expression and Cx43 gap junction formation. Overexpression of GJA1-20k improved mitochondrial membrane potential and respiration and lowered ROS production in Ang II-induced cardiomyocyte hypertrophy. These results demonstrate the importance of GJA1-20k in regulating gap junction formation and mitochondrial function in Ang II-induced cardiomyocyte hypertrophy, thus providing a novel therapeutic strategy for patients with cardiomyocyte hypertrophy.

Project description:BackgroundDuring the fresh cycles of in vitro fertilization and embryo transfer, a disturbance in the reproductive endocrine environment following controlled ovarian hyperstimulation (COH) is closely related to compromised endometrial receptivity. This is a major disadvantage for women during pregnancy. Based on the theory of traditional Chinese medicine, Bushen Huoxue recipe (BSHXR) has been indicated to facilitate embryo implantation.MethodsThe COH model (Kunming breed) was induced by injecting mice with pregnant mare serum gonadotrophin (0.4 IU/g) and human chorionic gonadotropin (1 IU/g), followed by treatment with BSHXR at three different concentrations (5.7, 11.4, and 22.8 g/kg), Bushen recipe (BSR) (5.7 g/kg), and Huoxue recipe (HXR) (5.7 g/kg). After successful mating, the pregnancy rate and implantation sites were examined on embryo day 8 (ED8), and the weight ratio of endometrium was calculated on ED4 midnight. Serum estrogen, progesterone, and endometrial PGE2 levels were measured using enzyme-linked immunosorbent assay. The endometrial microvasculature was evaluated using CD31 immunostaining. The protein and mRNA levels of the angiogenic factors in the endometrium were evaluated using western blot, immunohistochemistry, and polymerase chain reaction.ResultsIn the COH group, the pregnancy rate and implantation sites were significantly decreased, and abnormal serum hormone levels and impaired endometrial vascular development were observed. After BSHXR treatment, the supraphysiological serum progesterone level in COH mice was restored to normalcy. Moreover, the abnormal expression of the endometrial pro-angiogenic factors, including HIF1α, COX2-PGE2 pathway, and the down-stream factors, namely, MMP2, MMP9, TIMP2, and FGF2 after subjecting mice to COH was significantly improved after BSHXR treatment.ConclusionBSHXR could improve embryo implantation by regulating hormonal balance and modulating endometrial angiogenesis in mice, without inducing any side effects in normal pregnancy.

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Huoxue Qianyang Qutan recipe attenuates Ang II-induced cardiomyocyte hypertrophy by regulating reactive oxygen species production

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