Chronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy. Male wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy. High fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice. FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications.

Vascular adventitial fibroblasts (VAFs) contribute to vascular remodelling in hypertension. However, the mechanisms by which VAFs regulate vascular smooth muscle cells (VSMCs) in vascular remodelling are not well known. Here we report the crucial roles of extracellular nanoparticles exomeres (EMs) derived from VAFs in promoting VSMCs proliferation, migration and vascular remodelling in normotensive Wistar‐Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). VSMCs' proliferation and migration were enhanced by EMs of SHR via the uptake of EMs in VSMCs, but not by EMs of WKY. Proteomics analysis showed that increased osteopontin (OPN) content may be responsible for the roles of EMs of SHR, which was confirmed by the fact that EMs of SHR pretreated with OPN knockdown lost their roles in promoting VSMCs proliferation and migration. OPN successively promoted the phosphorylation of FAK, PI3K and AKT via acting on integrin αVβ3. Inhibition of integrin αVβ3, FAK, PI3K or AKT almost abolished the effects of EMs of SHR on VSMCs proliferation and migration. Knockdown of OPN in the carotid artery attenuated local vascular remodelling in SHR. Repetitive intravenous injection of EMs of SHR increased blood pressure and promoted vascular remodelling in WKY and SHR. We conclude that EMs from VAFs of SHR promote VSMCs proliferation, migration and vascular remodelling via transferring OPN and subsequently activating integrin αVβ3/FAK/PI3K/AKT signalling pathway.

Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca_V1.2 calcium channel is one primary pathway for Ca²⁺ influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca_V1.2 functions under hyperglycemic condition remains unknown. Here, Sprague–Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K⁺-induced arterial constriction and Ca_V1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K⁺-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca_V1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca_V1.2 channels exhibit hyperpolarized current–voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca_V1.2 channels in VSMCs and MAs. Notably, GS increases K⁺-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca_V1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. ELA (ELABELA) is a novel endogenous ligand for APJ (angiotensin receptor AT1–related receptor protein). However, the effects of ELA on TAD formation and development remain elusive. METHODS: Four-week-old C57BL/6J male mice were treated with β-aminopropionitrile monofumarate or β-aminopropionitrile monofumarate combined with Ang II (angiotensin II) to induce TAD models, and the aortic rupture occurred mainly in the descending thoracic region. ELA or saline was infused via osmotic minipumps into mice for 4 weeks. Transcriptomic studies and VSMC-derived conditioned medium were used to investigate the downstream molecular mechanisms of ELA. RESULTS: ELA infusion mitigated TAD development and prevented aortic media degradation in mice, which was reversed by APJ antagonist ML221. Exogenous ELA prevented the disruption of VSMC homeostasis under PDGF (platelet-derived growth factor) stimulation in VSMCs. Based on transcriptomic studies, we showed that ELA significantly inhibits NLRP3 (NLR family pyrin domain-containing 3)/IL (interleukin)-1β pathway activation and modulates NET (neutrophil extracellular trap) formation in vivo and in vitro. In human neutrophils, ELA significantly inhibited NETs’ formation, which is prevented by reactive oxidative species supplementation. Using VSMC-derived conditioned medium, we showed that NLRP3/IL-1β–related NETs’ formation connects cellular signaling from VSMCs to neutrophils, leading to disruption of VSMC homeostasis. Notably, ELA was downregulated in both plasma and aortic tissues of human TAD, and lower plasma ELA levels were associated with an increased risk of TAD. CONCLUSIONS: We provide evidence that ELA prevents TAD progression and aortic medial degeneration, primarily by maintaining VSMC homeostasis, which may be linked to the inhibition of NETosis in neutrophils and NLRP3/IL-1β–related cellular signaling between VSMCs and neutrophils. ELA shows promise as a target for pharmacological therapy and diagnostic TAD management.