Aldehyde dehydrogenase 2 serves as a key cardiometabolic adaptation regulator in response to plateau hypoxia in mice.

High-altitude heart disease (HAHD) is a complex pathophysiological condition related to systemic hypobaric hypoxia in response to transitioning to high altitude. Hypoxia can cause myocardial metabolic dysregulation, leading to an increased risk of heart failure and sudden cardiac death. Aldehyde dehydrogenase 2 (ALDH2) could regulate myocardial energy metabolism and plays a protective role in various cardiovascular diseases. This study aims to determine the effects of plateau hypoxia (PH) on cardiac metabolism and function, investigate the associated role of ALDH2, and explore potential therapeutic targets. We discovered that PH significantly reduced survival rate and cardiac function. These effects were exacerbated by ALDH2 deficiency. PH also caused a shift in the myocardial fuel source from fatty acids to glucose; ALDH2 deficiency impaired this adaptive metabolic shift. Untargeted/targeted metabolomics and transmission electron microscopy revealed that ALDH2 deficiency promoted myocardial fatty-acid deposition, leading to enhanced fatty-acid transport, lipotoxicity and mitochondrial dysfunction. Furthermore, results showed that ALDH2 attenuated PH-induced impairment of adaptive metabolic programs through 4-HNE/CPT1 signaling, and the CPT1 inhibitor etomoxir significantly ameliorated ALDH2 deficiency-induced cardiac impairment and improved survival in PH mice. Together, our data reveal ALDH2 acts as a key cardiometabolic adaptation regulator in response to PH. CPT1 inhibitor, etomoxir, may attenuate ALDH2 deficiency-induced effects and improved cardiac function in response to PH.

Blood pressure control and left ventricular echocardiographic progression in hypertensive patients: an 18-month follow-up study.

Objectives: The impact of blood pressure (BP) control and its timing on left ventricular (LV) structure and function remains unclear. The present study was to evaluate whether BP control correlated with conventional LV geometry and function indexes or global longitudinal strain (GLS) progression, and when echocardiographic changes would occur in essential hypertension. Methods and results: A total of 62 participants (mean age 55.2 ± 11.5, male 71.0%) with uncontrolled hypertension were enrolled in the longitudinal study. Patients were followed up at the 6-month and 18-month, when echocardiographic measurements were performed and BP control was evaluated during the follow up period. At the 6- and 18-month examination, we divided the hypertensive patients into two groups as BP controlled and uncontrolled group. Patients with BP uncontrolled (n = 33) had higher LV mass index (P = 0.02), higher left atrial volume index (P = 0.01), worse GLS (P = 0.005) and GLS changes (P = 0.003) compared with controlled BP (n = 29) at the 6-month follow-up examination. Patients with uncontrolled BP (n = 25) had higher LV mass index (P = 0.001), higher LV mass index changes (P = 0.01), higher relative wall thickness (P = 0.01), higher E/e' (P = 0.046), worse GLS (P = 0.02) and GLS changes (P = 0.02) compared to BP controlled group (n = 24) at the 18-month follow-up examination. GLS changes were associated with BP control (ß = 0.370, P = 0.004 at the 6-month examination and ß = 0.324, P = 0.02 at the 18-month examination, respectively) in stepwise multivariate regression analysis. LV mass index changes was corelated with systolic BP (ß = 0.426, P = 0.003) at the 18-month follow-up examination in stepwise multivariate regression analysis. Neither was GLS changes nor LV mass index changes were related to antihypertensive medication class, including combination therapy in 6- or 18-month follow up examination. Conclusions: Our findings offer new clinical evidence on the association of BP control with echocardiographic changes in hypertensive patients, and, in particular, support the view that GLS progression was earlier and subtler than conventional LV geometry and function parameters. GLS changes were significant between BP controlled and uncontrolled patients even in 6-month follow-up period.

C-atrial natriuretic peptide (ANP)4-23 attenuates renal fibrosis in deoxycorticosterone-acetate-salt hypertensive mice.

Epithelial-mesenchymal transition (EMT) plays a critical role in hypertension-induced renal fibrosis, a final pathway that leads to end-stage renal failure. C-Atrial natriuretic peptide (ANP)4-23, a specific agonist of natriuretic peptide receptor-C (NPR-C), has been reported to have protective effects against hypertension. However, the role of C-ANP4-23 in hypertension-associated renal fibrosis has not yet been elucidated. In this study, mice were randomly divided into SHAM group, DOCA-salt group and DOCA-salt + C-ANP4-23 group. Renal morphology changes, renal function and fibrosis were detected. Human proximal tubular epithelial cells (HK2) stimulated by aldosterone were used for cell function and mechanism study. The DOCA-salt treated mice exhibited hypertension, kidney fibrosis and renal dysfunction, which were attenuated by C-ANP4-23. Moreover, C-ANP4-23 inhibited DOCA-salt treatment-induced renal EMT as evidenced by decrease of the mesenchymal marker alpha-smooth muscle actin (ACTA2) and vimentin and increase of epithelial cell marker E-cadherin. In HK2 cells, aldosterone induced EMT response, which was also suppressed by C-ANP4-23. The key transcription factors (twist, snail, slug and ZEB1) involved in EMT were increased in the kidney of DOCA-salt-treated mice, which were also suppressed by C-ANP4-23. Mechanistically, C-ANP4-23 inhibited the aldosterone-induced translocation of MR from cytosol to nucleus without change of MR expression. Furthermore, C-ANP4-23 rescued the enhanced expression of NADPH oxidase (NOX) 4 and oxidative stress after aldosterone stimulation. Aldosterone-induced Akt and Erk1/2 activation was also suppressed by C-ANP4-23. Our data suggest that C-ANP4-23 attenuates renal fibrosis, likely through inhibition of MR activation, enhanced oxidative stress and Akt and Erk1/2 signaling pathway.

An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction.

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Liraglutide promotes angiogenesis in adipose tissue via suppression of adipocyte-derived IL-6.

Accumulating evidence suggests that Liraglutide is a favorable treatment for obese people. Obesity induces cellular senescence and accumulated senescent adipocytes in adipose tissue. However, the role of Liraglutide in adipose tissue (AT) senescence and the underlying mechanisms remain obscure. In this study, we found that HFD induces adipocyte senescence and impaired angiogenesis in AT. The deleterious effects provoked unhealthy adipose tissue remodeling and metabolic disturbance. In contrast, treatment of Liraglutide promoted weight reduction, alleviated adipose tissue senescence, and improved angiogenesis in AT. Notably, we demonstrated that Liraglutide promotes angiogenesis in AT dependent on adipocyte-derived IL-6. These findings revealed distinctive roles of Liraglutide in the regulation of adipocyte senescence and provide a therapeutic potential to obesity-associated metabolic disorders.

Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.

Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.

Prevalence and clinical characteristics of renovascular hypertension associated with fibromuscular dysplasia in China.

OBJECTIVES: The aim of this study was to investigate the clinical characteristics of renal artery fibromuscular dysplasia (FMD) in patients in China and identify the cure rate of hypertension after angioplasty. METHODS: Consecutive hypertensive patients with renal artery stenosis caused by FMD who underwent catheter-based angiography, and were followed at two Chinese referral centres, were retrospectively analysed. All patients underwent a detailed investigation, including demographic characteristics, clinical characteristics, biochemical sampling, Doppler ultrasonography of carotid arteries, magnetic resonance angiography (MRA) of the intracranial artery, and CTA or MRA of the abdominal artery and catheter-based renal angiography. Patients were routinely followed up at 1 month, 6 months and every year after the procedure. RESULTS: Among 245 study participants, with a mean diagnosed age of 26.9 ±â€Š9.9 years, 137 (55.9%) were women, and 38 (15.5%) were children. All patients were diagnosed with hypertension at a mean age of 23.4 ±â€Š8.4 years. There were 73.5% focal and 15.2% multivessel cases. Aneurysms, arterial dissections and total occlusions were found in 21.6, 4.1 and 12.2% of patients, respectively. Patients with multifocal FMD were older (26.0 vs. 23.7 years, P  = 0.021) and more often female (70.8 vs. 50.6%, P  = 0.004). Among children with renal FMD, 55.2% were men, and 86.8% were focal. After a median follow-up of 7.0 years, multifocal FMD had a higher cure rate of hypertension than focal FMD after revascularization (71.7 vs. 55.8%, P  = 0.032). CONCLUSION: In a cohort of mostly young Chinese patients, the prevalence of hypertension associated with renal FMD is similar in both sexes. Focal FMDs were more frequent than the multifocal ones and, after angioplasty, were associated with a worse blood pressure outcome.

Intravascular ultrasound provides additional insights in the hypertensive patients with focal renal artery fibromuscular dysplasia.

To date, few study has defined the exact role or utility of intravascular ultrasound (IVUS) in the diagnosis and treatment of renal artery fibromuscular dysplasia (FMD). We investigated whether using an IVUS would provide additional insights in the hypertensive patients with focal renal artery FMD. A prospective, observational study, including all patients with focal renal artery FMD admitted to the Ruijin hospital during 6 consecutive years (2015-2021). Based on IVUS imaging, focal FMD patients were classified as two subtypes: intima-media thickening (IMT) and negative remodeling (NR) of the whole vessel. A total of 36 consecutive patients (24 ± 7, 13-39 years) with focal renal artery FMD were enrolled. Angiographic unifocal type was present in 22 (61.1%) patients and tubular type was present in 14 (38.9%) patients. Among 22 patients with unifocal, IVUS showed that 18 (81.8%) had IMT and 4 (18.2%) had NR. 14 patients with tubular, IVUS showed 3 (21.4%) had IMT and 11 (78.6%) had NR. No difference in age of onset, gender, BMI, initial BP levels were found between IMT and NR subtypes. However, hypertension cure rates of short-term (48 h after angioplasty) (76.2% vs. 26.7%, p = 0.004) and long-term (1-6years) (90.5% vs. 20.0%, p < 0.001) were higher in patients with IMT than in those with NR subtype. In present study, we described a new classification of focal renal artery FMD into IMT or NR subtype based on IVUS. Renal FMD Patients with IMT subtype were more likely to achieve cure of hypertension. We investigated whether using an IVUS would provide additional insights in the hypertensive patients with focal renal artery FMD. A new classification of focal renal artery FMD into IMT or NR subtype based on IVUS was described. Renal FMD Patients with IMT subtype were more likely to achieve cure of hypertension.

Mitogen-Activated Protein Kinases Mediate Adventitial Fibroblast Activation and Neointima Formation via GATA4/Cyclin D1 Axis.

PURPOSE: Activation of mitogen-activated protein kinases (MAPKs) by pathological stimuli participates in cardiovascular diseases. Dysfunction of adventitial fibroblast has emerged as a critical regulator in vascular remodeling, while the potential mechanism remains unclear. In this study, we sought to determine the effect of different activation of MAPKs in adventitial fibroblast contributing to neointima formation. METHODS: Balloon injury procedure was performed in male 12-week-old Sprague-Dawley rats. After injury, MAPK inhibitors were applied to the adventitia of injured arteries to suppress MAPK activation. Adventitial fibroblasts were stimulated by platelet-derived growth factor-BB (PDGF-BB) with or without MAPK inhibitors. RNA sequencing was performed to investigate the change of pathway and cell function. Wound healing, transwell assay, and flow cytometry were used to analyze adventitial fibroblast function. RESULTS: Phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular regulated kinases 1/2 (ERK1/2) was increased in injured arteries after balloon injury. In primary culture of adventitial fibroblasts, PDGF-BB increased phosphorylation of p38, JNK, ERK1/2, and extracellular regulated kinase 5 (ERK5) in a short time, which was normalized by their inhibitors respectively. Compared with the injury group, perivascular administration of four MAPK inhibitors significantly attenuated neointima formation by quantitative analysis of neointimal area, intima to media (I/M) ratio, and lumen area. RNA sequencing of adventitial fibroblasts treated with PDGF-BB with or without four inhibitors demonstrated differentially expressed genes involved in multiple biological processes, including cell adhesion, proliferation, migration, and inflammatory response. Wound healing and transwell assays showed that four inhibitors suppressed PDGF-BB-induced adventitial fibroblast migration. Cell cycle analysis by flow cytometry demonstrated that JNK, ERK1/2, and ERK5 but not p38 inhibitor blocked PDGF-BB-induced G1 phase release associated with decrease expression of cell cycle protein Cyclin D1 and transcription factor GATA4. Moreover, four inhibitors decreased macrophage infiltration into adventitia and monocyte chemoattractant protein-1 (MCP-1) expression. CONCLUSION: These results suggest that MAPKs differentially regulate activation of adventitial fibroblast through GATA4/Cyclin D1 axis that participates in neointima formation.

Brown Adipocyte ADRB3 Mediates Cardioprotection via Suppressing Exosomal iNOS.

BACKGROUND: The ADRB3 (ß3-adrenergic receptors), which is predominantly expressed in brown adipose tissue (BAT), can activate BAT and improve metabolic health. Previous studies indicate that the endocrine function of BAT is associated with cardiac homeostasis and diseases. Here, we investigate the role of ADRB3 activation-mediated BAT function in cardiac remodeling. METHODS: BKO (brown adipocyte-specific ADRB3 knockout) and littermate control mice were subjected to Ang II (angiotensin II) for 28 days. Exosomes from ADRB3 antagonist SR59230A (SR-exo) or agonist mirabegron (MR-exo) treated brown adipocytes were intravenously injected to Ang II-infused mice. RESULTS: BKO markedly accelerated cardiac hypertrophy and fibrosis compared with control mice after Ang II infusion. In vitro, ADRB3 KO rather than control brown adipocytes aggravated expression of fibrotic genes in cardiac fibroblasts, and this difference was not detected after exosome inhibitor treatment. Consistently, BKO brown adipocyte-derived exosomes accelerated Ang II-induced cardiac fibroblast dysfunction compared with control exosomes. Furthermore, SR-exo significantly aggravated Ang II-induced cardiac remodeling, whereas MR-exo attenuated cardiac dysfunction. Mechanistically, ADRB3 KO or SR59230A treatment in brown adipocytes resulted an increase of iNOS (inducible nitric oxide synthase) in exosomes. Knockdown of iNOS in brown adipocytes reversed SR-exo-aggravated cardiac remodeling. CONCLUSIONS: Our data illustrated a new endocrine pattern of BAT in regulating cardiac remodeling, suggesting that activation of ADRB3 in brown adipocytes offers cardiac protection through suppressing exosomal iNOS.

Association of Nighttime Masked Uncontrolled Hypertension With Left Ventricular Hypertrophy and Kidney Function Among Patients with Chronic Kidney Disease Not Receiving Dialysis.

Importance: Nighttime hypertension is prevalent and associated with adverse outcomes in patients with chronic kidney disease (CKD), but nighttime hypertension, a subtype of masked uncontrolled hypertension (MUCH), is often undetected among patients with controlled office blood pressure. Little attention has been paid to patients with CKD and nighttime MUCH. Objective: To investigate the prevalence of nighttime MUCH and its associations with cardiovascular and kidney outcomes in patients with CKD who were not receiving dialysis. Design, Setting, and Participants: This retrospective cohort study included patients with nondialysis CKD and hypertension, enrolled in Shanghai, China, from July 2012 through November 2020 and followed up for a median of 39 months. Exposures: Participants were classified as having controlled hypertension, sustained hypertension, and MUCH, which was further divided into isolated nighttime MUCH and day-night MUCH, assessed by office and ambulatory blood pressure monitoring. Main Outcomes and Measures: Left ventricular hypertrophy (LVH) was determined by echocardiography. The composite kidney outcome consisted of end-stage kidney diseases (ESKD) and a reduction of estimated glomerular filtration rate (eGFR) by 50% or more. Logistic and Cox regression assessed the associations of hypertension subtypes with LVH and kidney outcomes. Results: The 675 patients (425 [63.0%] men; mean [SD] age, 50.8 [15.9] years; mean [SD] eGFR, 61.6 [29.4] mL/min/1.73 m2) included 125 (19.3%) with controlled hypertension, 244 (37.6%) with MUCH, and 280 (43.1%) sustained hypertension. Among patients with MUCH, 2 (0.8%) had isolated daytime MUCH, 154 (63.1%) had isolated nighttime MUCH, and 88 (36.1%) had day-night MUCH. During a median (IQR) follow-up of 39 (19-64) months, 130 composite kidney events, including 97 ESKD events, occurred. Compared with controlled hypertension, MUCH and sustained hypertension were associated with LVH (eg, MUCH: odds ratio [OR], 2.94; 95% CI, 1.18-7.34; P = .02) and the composite kidney outcome (eg, MUCH: hazard ratio [HR], 4.12; 95% CI, 1.75-9.73; P = .001) after adjustment for age, sex, proteinuria, eGFR, and other baseline risk factors. Multivariate-adjusted associations were also significant between day-night MUCH and LVH (OR, 3.26; 95% CI, 1.15-9.25) and between isolated nighttime MUCH and the composite kidney outcome (HR, 4.27; 95% CI, 1.69-10.77). Conclusions and Relevance: In this cohort study, nighttime MUCH was common and associated with LVH and poor kidney outcomes among patients with hypertension and nondialysis CKD. These findings suggest that ambulatory blood pressure monitoring was inadequately used in patients with CKD and hypertension, calling for more widespread use, even in patients with controlled office hypertension.

The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism.

Background: Adrenal venous sampling (AVS) is recognized as the gold standard for subtyping primary aldosteronism (PA), but its invasive nature and technical challenges limit its availability. A recent study reported that sodium chloride cotransporter (NCC) in urinary extracellular vesicles (uEVs) is a promising marker for assessing the biological activity of aldosterone and can be treated as a potential biomarker of PA. The current study was conducted to verify the hypothesis that the expression of NCC and its phosphorylated form (pNCC) in uEVs are different in various subtypes and genotypes of PA and can be used to select AVS candidates. Methods: A total of 50 patients with PA were enrolled in the study. Urinary extracellular vesicles (uEVs) were isolated from spot urine samples using ultracentrifugation. NCC and pNCC expressions were tested in patients diagnosed with PA who underwent AVS. Sanger sequencing of KCNJ5 was performed on DNA extracted from adrenal adenoma. Results: pNCC (1.89 folds, P<.0001) and NCC (1.82 folds, P=0.0002) was more abundant in the uEVs in the high lateralization index (h-LI, ≥ 4) group than in the low LI (l-LI, < 4) group. Carriers of the somatic KCNJ5 mutations, compared with non-carriers, had more abundant pNCC expression (2.16 folds, P=0.0039). Positive correlation between pNCC abundance and plasma aldosterone level was found in this study (R = 0.1220, P = 0.0129). Conclusions: The expression of pNCC in uEVs in patients with PA with various subtypes and genotypes was different. It can be used as biomarker of AVS for PA subtyping.

AIFM1, negatively regulated by miR-145-5p, aggravates hypoxia-induced cardiomyocyte injury.

BACKGROUND: Hypoxia-induced apoptosis is linked to the pathogenesis of myocardial infarction. The role of apoptosis-inducing factor mitochondria associated 1 (AIFM1) in cardiomyocyte injury remains unclear. This study was aimed at probing into the role and the underlying regulatory mechanism of AIFM1 in myocardial injury. METHODS: H9c2 cardiomyocytes and C57BL/6 mice were used for myocardial hypoxic/ischemic injury and myocardial infarction animal models. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate the expression levels of AIFM1 mRNA and miR-145-5p. Western blot was used for examining the expression levels of AIFM1, caspase-3, cleaved caspase-3, p-53, and γ-H2AX. Cell viability was examined by cell counting kit-8 (CCK-8) assay and BrdU assay. Interaction between AIFM1 and miR-145-5p was determined by bioinformatics analysis, qRT-PCR, Western blot, and dual-luciferase reporter assay. RESULTS: AIFM1 expression was markedly highly elevated, while miR-145-5p expression was significantly down-regulated in the myocardial infarction animal model and H9c2 cells under hypoxia. Augmentation of AIFM1 led to a dramatic decrease of cell viability, accompanied by an increase of the secretion of the inflammatory cytokines IL-1ß, TNF-α, IL-6, and the expression of cleaved caspase-3. Furthermore, AIFM1 was identified as a target of miR-145-5p. In addition, miR-145-5p/AIFM1 axis regulated the expression of p53. CONCLUSION: AIFM1 may exacerbate myocardial ischemic injury by promoting inflammation and the injury of cardiomyocytes, and its up-regulation may be partly due to the down-regulation of miR-145-5p.

Recurrence of Primary Aldosteronism 10 Years After Left Adrenalectomy for Aldosterone-Producing Adenoma: A Case Report.

A 29-year-old female patient diagnosed with primary aldosteronism (PA) in 2004 underwent complete adrenalectomy for left aldosterone-producing adenoma (APA) confirmed by hematoxylin and eosin (HE) and CYP11B2 staining. Her hypokalemia was corrected, and her blood pressure (BP) normalized and maintained without medication for 10 years. In 2014, her BP became elevated again, and a recurrence of PA with an adenoma on the right adrenal gland was discovered by computed tomography scan. She underwent partial right adrenalectomy in 2018 due to unsatisfactory BP control with medication and gradually enlarging adenoma. The resected adrenal tissue contained a CYP11B2 staining positive APA. Her BP was then controlled by two drugs. Sanger sequencing of DNA extracted from tissue slices revealed that both left and right adenomas carried the same aldosterone-driver KCNJ5 gene mutation, but with different nucleotide changes. We suggest that patients who undergo adrenalectomy for APA should be followed up for life.

Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3.

Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.

Krüppel-Like Factor 15/Interleukin 11 Axis-Mediated Adventitial Remodeling Depends on Extracellular Signal-Regulated Kinases 1 and 2 Activation in Angiotensin II-Induced Hypertension.

Background Adventitial remodeling is a pathological hallmark of hypertension that results in target organ damage. Activated adventitial fibroblasts have emerged as critical regulators in this process, but the precise mechanism remains unclear. Methods and Results Interleukin 11 (IL-11) knockout and wild-type mice were subjected to angiotensin II (Ang II) infusion to establish models of hypertension-associated vascular remodeling. IL-11 mRNA and protein were increased especially in the adventitia in response to Ang II. Compared with wild-type mice, Ang II-treated IL-11 knockout mice showed amelioration of vascular hypertrophy, adventitial fibrosis, macrophage infiltration, and inflammatory factor expression. Recombination mouse IL-11 exacerbated adventitial fibrosis in Ang II-infused wild-type mice. Interestingly, IL-11 neutralizing antibody attenuated adventitial fibrosis, macrophage infiltration, and inflammatory factor expression after Ang II infusion for 7 days. Mechanistically, in primary cultured adventitial fibroblasts, Krüppel-like factor 15 negatively regulated Ang II-induced IL-11 expression. Ang II increased extracellular signal-regulated kinases 1 and 2 activation, especially in adventitia, and caused biphasic extracellular signal-regulated kinases 1 and 2 activation in adventitial fibroblasts. A rapid and early activation increased IL-11 production through decreasing Krüppel-like factor 15 expression, which, in turn, induced the second extracellular signal-regulated kinases 1 and 2 activation, resulting in posttranscriptional profibrotic gene expression. Conclusions These results demonstrate that extracellular signal-regulated kinases 1 and 2 activation is important for Krüppel-like factor 15-mediated IL-11 expression in adventitial fibroblasts to promote adventitial remodeling in Ang II-induced hypertension. Therefore, targeting the Krüppel-like factor 15/IL-11 axis might serve as a new therapeutic strategy for vascular diseases.

Cardiac Fibroblast-Specific Knockout of PGC-1α Accelerates AngII-Induced Cardiac Remodeling.

Cardiac remodeling consisted of ventricular hypertrophy and interstitial fibrosis is the pathological process of many heart diseases. Fibroblasts as one of the major cells in the myocardium regulate the balance of the generation and degeneration of collagen, and these cells transform toward myofibroblasts in pathological state, contributing to the remodeling of the heart. Peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1α (PGC-1α) is vital to the function of mitochondria, which contributes to the energy production and reactive oxidative species (ROS)-scavenging activity in the heart. In this study, we found that fibroblast-specific PGC-1α KO induced cardiac remodeling especially fibrosis, and Angiotensin II (AngII) aggravated cardiac fibrosis, accompanied with a high level of oxidative stress response and inflammation.

PDGF-D activation by macrophage-derived uPA promotes AngII-induced cardiac remodeling in obese mice.

Obesity-induced secretory disorder of adipose tissue-derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, regulates cardiac remodeling in angiotensin II (AngII)-infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue as well as more severe cardiac remodeling compared with control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow-specific uPA knockdown decreased active PDGF-DD levels in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.