Adaptor protein HIP-55 promotes macrophage M1 polarization through promoting AP-1 complex activation.

Overwhelming macrophage M1 polarization induced by malfunction of the renin-angiotensin-aldosterone system (RAAS) initiates inflammatory responses, which play a crucial role in various cardiovascular diseases. However, the underlying regulatory mechanism remains elusive. Here, we identified adaptor protein HIP-55 as a critical regulator of macrophage M1 polarization. The expression of HIP-55 was upregulated in M1 macrophage induced by Ang II. Overexpression of HIP-55 significantly promoted Ang II-induced macrophage M1 polarization, whereas genetic deletion of HIP-55 inhibited the Ang II-induced macrophage M1 polarization. Mechanistically, HIP-55 facilitated activator protein-1 (AP-1) complex activation induced by Ang II via promoting ERK1/2 and JNK phosphorylation. Moreover, blocking AP-1 complex activation can attenuate the function of HIP-55 in macrophage polarization. Collectively, our results reveal the role of HIP-55 in macrophage polarization and provide potential therapeutic insights for cardiovascular diseases associated with RAAS dysfunction.

Src tyrosine kinase promotes cardiac remodeling induced by chronic sympathetic activation.

Cardiac remodeling serves as the underlying pathological basis for numerous cardiovascular diseases and represents a pivotal stage for intervention. The excessive activation of ß-adrenergic receptors (ß-ARs) assumes a crucial role in cardiac remodeling. Nonetheless, the underlying molecular mechanisms governing ß-AR-induced cardiac remodeling remain largely unresolved. In the present study, we identified Src tyrosine kinase as a key player in the cardiac remodeling triggered by excessive ß-AR activation. Our findings demonstrated that Src mediates isoproterenol (ISO)-induced cardiac hypertrophy, fibrosis, and inflammation in vivo. Furthermore, Src facilitates ß-AR-mediated proliferation and transdifferentiation of cardiac fibroblasts, and hypertrophy and cardiomyocytes in vitro. Subsequent investigations have substantiated that Src mediates ß-AR induced the extracellular signal-regulated protein kinase (ERK1/2) signaling pathway activated by ß-AR. Our research presents compelling evidence that Src promotes ß-AR-induced cardiac remodeling in both in vivo and in vitro settings. It establishes the promoting effect of the ß-AR/Src/ERK signaling pathway on overall cardiac remodeling in cardiac fibroblasts and underscores the potential of Src as a therapeutic target for cardiac remodeling.

Aortic smooth muscle TRPV4 channels regulate vasoconstriction in high salt-induced hypertension.

Recent studies have focused on the contribution of vascular endothelial transient receptor potential vanilloid 4 (TRPV4) channels to hypertension. However, in hypertension, TRPV4 channels in vascular smooth muscle remain unexplored. In the present study, we performed wire myograph experiments in isolated aortas from endothelial cell specific TRPV4 channel knockout (TRPV4EC-/-) mice to demonstrate that GSK1016790A (a specific TRPV4 channel agonist) triggered aortic smooth muscle-dependent contractions from mice on a normal-salt diet, and the contractions were enhanced in high-salt diet (HSD) mice. Intracellular Ca2+ concentration ([Ca2+]i) and Ca2+ imaging assays showed that TRPV4-induced [Ca2+]i was significantly higher in aortic smooth muscle cells (ASMCs) from HSD-induced hypertensive mice, and application of an inositol trisphosphate receptor (IP3R) inhibitor markedly attenuated TRPV4-induced [Ca2+]i. IP3R2 expression was enhanced in ASMCs from HSD-induced hypertensive mice and the contractile response induced by TRPV4 was inhibited by the IP3R inhibitor. Whole-transcriptome analysis by RNA-seq and western blot assays revealed the involvement of interferon regulatory factor 7 (IRF7) in TRPV4-IRF7-IP3R2 signaling in HSD-induced hypertension. These results suggested that TRPV4 channels regulate smooth muscle-dependent contractions in high salt-induced hypertension, and this contraction involves increased [Ca2+]i, IP3R2, and IRF7 activity. Our study revealed a considerable effect of TRPV4 channels in smooth muscle-dependent contraction in mice during high-salt induced hypertension.

Endothelial Transient Receptor Potential Canonical Channel Regulates Angiogenesis and Promotes Recovery After Myocardial Infarction.

Background Transient receptor potential canonical (TRPC) channels play a role in angiogenesis. However, the involvement of TRPC1 in myocardial infarction (MI) remains unclear. The present study was aimed at investigating whether TRPC1 can improve the recovery of cardiac function via prompting angiogenesis following MI. Methods and Results In vitro, coronary artery endothelial cells from floxed TRPC1 mice and endothelial cell-specific TRPC1 channel knockout mice were cultured to access EC angiogenesis. Both EC tube formation and migration were significantly suppressed in mouse coronary artery endothelial cells from endothelial cell-specific TRPC1 channel knockout mice. In vivo, coronary artery endothelial cells from floxed TRPC1 and endothelial cell-specific TRPC1 channel knockout mice were subjected to MI, then echocardiography, triphenyltetrazolium chloride staining and immunofluorescence were performed to assess cardiac repair on day 28. Endothelial cell-specific TRPC1 channel knockout mice had higher ejection fraction change, larger myocardial infarct size, and reduced capillary density in the infarct area compared with coronary artery endothelial cells from floxed TRPC1 mice. Furthermore, we found underlying regulation by HIF-1α (hypoxic inducible factor-1α) and MEK-ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) that could be the mechanism for the angiogenetic action of TRPC1. Significantly, treatment with dimethyloxaloylglycine, an activator of HIF-1α, induced cardiac improvement via the HIF-1α-TRPC1-MEK/ERK pathway in MI mice. Conclusions Our study demonstrated TRPC1 improves cardiac function after MI by increasing angiogenesis via the upstream regulator HIF-1α and downstream MEK/ERK, and dimethyloxaloylglycine treatment has protective effect on MI through the HIF-1α-TRPC1-MEK/ERK pathway.

Construction of High-Density Genetic Map and Identification of QTLs Associated with Seed Vigor after Exposure to Artificial Aging Conditions in Sweet Corn Using SLAF-seq.

Seed vigor is a key factor that determines the quality of seeds, which is of great significance for agricultural production, with the potential to promote growth and productivity. However, the underlying molecular mechanisms and genetic basis for seed vigor remain unknown. High-density genetic linkage mapping is an effective method for genomic study and quantitative trait loci (QTL) mapping. In this study, a high-density genetic map was constructed from a 148 BC4F3 population cross between 'M03' and 'M08' strains based on specific-locus amplified fragment (SLAF) sequencing. The constructed high-density genetic linkage map (HDGM) included 3876 SNP markers on ten chromosomes covering 2413.25 cM in length, with a mean distance between markers of 0.62 cM. QTL analysis was performed on four sweet corn germination traits that are related to seed vigor under artificial aging conditions. A total of 18 QTLs were identified in two seasons. Interestingly, a stable QTL was detected in two seasons on chromosome 10-termed qGR10-within an interval of 1.37 Mb. Within this interval, combined with gene annotation, we found four candidate genes (GRMZM2G074309, GRMZM2G117319, GRMZM2G465812, and GRMZM2G343519) which may be related to seed vigor after artificial aging.

Intravenous administration of achyranthes bidentata polypeptides supports recovery from experimental ischemic stroke in vivo.

BACKGROUND: Achyranthes bidentata Blume (A. bidentata) is a commonly prescribed Chinese medicinal herb. A. bidentata polypeptides (ABPP) is an active composite constituent, separated from the aqueous extract of A. bidentata. Our previous studies have found that ABPP have the neuroprotective function in vitro and in rat middle cerebral artery occlusion (MCAO) model in attenuating the brain infract area induced by focal ischemia-reperfusion. However, the ultimate goal of the stroke treatment is the restoration of behavioral function. Identifying behavioral deficits and therapeutic treatments in animal models of ischemic stroke is essential for potential translational applications. METHODOLOGY AND PRINCIPAL FINDINGS: The effect of ABPP on motor, sensory, and cognitive function in an ischemic stroke model with MCAO was investigated up to day 30. The function recovery monitored by the neurological deficit score, grip test, body asymmetry, beam-balancing task, and the Morris Water Maze. In this study, systemic administration of ABPP by i.v after MCAO decreased the neurological deficit score, ameliorated the forepaw muscle strength, and diminished the motor and sensory asymmetry on 7(th) and 30(th) day after MCAO. MCAO has been observed to cause prolonged disturbance of spatial learning and memory in rats using the MWM, and ABPP treatment could improve the spatial learning and memory function, which is impaired by MCAO in rats, on 30(th) day after MCAO. Then, the viable cells in CA1 region of hippocampus were counted by Nissl staining, and the neuronal cell death were significantly suppressed in the ABPP treated group. CONCLUSION: ABPP could improve the recovery of sensory, motor and coordination, and cognitive function in MCAO-induced ischemic rats. And this recovery had a good correlation to the less of neuronal injury in brain.