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1.
bioRxiv ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39005289

RESUMO

Type 2 diabetics have an increased prevalence of hypertension and nondipping blood pressure (BP), which worsen cardiovascular outcomes. Exenatide, a short acting glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes, also demonstrates blood pressure (BP)-lowering effects. However, the mechanisms behind this and the impact of administration timing on BP dipping remain unclear. We investigated the effects of exenatide intraperitoneal injected at light onset (ZT0) or dark onset (ZT12) in diabetic (db/db) mice and nondiabetic controls. Using radio-telemetry and BioDAQ cages, we continuously monitored BP and food intake. Db/db mice exhibited non-dipping BP and increased food intake. ZT0 exenatide administration restored BP dipping by specifically lowering light-phase BP, while ZT12 exenatide reversed dipping by lowering dark-phase BP. These effects correlated with altered food intake patterns, and importantly, were abolished when food access was removed. Additionally, urinary norepinephrine excretion, measured by HPLC, was significantly reduced 6 hours post-exenatide at both ZT0 and ZT12, suggesting sympathetic nervous system involvement. Notably, combining exenatide with either ganglionic blocker mecamylamine or α-blocker prazosin did not enhance BP reduction beyond the individual effects of each blocker. These findings reveal that exenatide, when administered at light onset, restores BP dipping in db/db mice by suppressing light-phase food intake and sympathetic activity. Importantly, the efficacy of exenatide is dependent on food availability and its timing relative to circadian rhythms, highlighting the potential for chronotherapy in optimizing GLP-1RA- based treatments for type 2 diabetes and hypertension. Article Highlights: Maintaining a normal blood pressure (BP) circadian rhythm is vital for cardiovascular health, but diabetes often disrupts this rhythm. The effect of exenatide, a GLP-1 receptor agonist (GLP-1RA), on BP rhythm in diabetes is uncertain.This study investigates the impact of exenatide administration timing on BP patterns in diabetic db/db mice.Findings indicate that exenatide given at the onset of rest restores normal BP dipping, while at the start of the active phase worsens BP rhythm by modulating food intake and sympathetic activity.Timing GLP-1 RA administration may optimize BP control and provide cardiovascular benefits for type 2 diabetes patients.

2.
J Clin Invest ; 134(15)2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38900572

RESUMO

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms (AAs), a devastating vascular disease with a higher prevalence and fatality rate in men than in women. However, the mechanism by which androgen mediates AAs is largely unknown. Here, we found that male, not female, mice developed AAs when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (ARs) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and AAs. Furthermore, we demonstrated that administration of anti-PD-1 Ab and adoptive PD-1-deficient T cell transfer reinstated Aldo-salt-induced AAs in orchiectomized mice and that genetic deletion of PD-1 exacerbated AAs induced by a high-fat diet and angiotensin II (Ang II) in nonorchiectomized mice. Mechanistically, we discovered that the AR bound to the PD-1 promoter to suppress the expression of PD-1 in the spleen. Thus, our study unveils a mechanism by which androgen aggravates AAs by suppressing PD-1 expression in T cells. Moreover, our study suggests that some patients with cancer might benefit from screenings for AAs during immune checkpoint therapy.


Assuntos
Androgênios , Aneurisma Aórtico , Receptor de Morte Celular Programada 1 , Receptores Androgênicos , Animais , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Camundongos , Masculino , Feminino , Androgênios/farmacologia , Androgênios/metabolismo , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Aldosterona/metabolismo , Camundongos Knockout , Humanos , Angiotensina II/farmacologia
3.
Sci Rep ; 13(1): 2748, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36797364

RESUMO

Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.


Assuntos
Resistência à Insulina , Oligonucleotídeos Antissenso , Animais , Masculino , Camundongos , Antígeno CD47/metabolismo , Dieta Hiperlipídica , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Antissenso/genética
4.
bioRxiv ; 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36711644

RESUMO

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.

5.
Front Nutr ; 9: 969345, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36159491

RESUMO

Disruption of blood pressure (BP) circadian rhythm, independent of hypertension, is emerging as an index for future target organ damage and is associated with a higher risk of cardiovascular events. Previous studies showed that changing food availability time alters BP rhythm in several mammalian species. However, the underlying mechanisms remain largely unknown. To address this, the current study specifically investigates (1) the relationship between rhythms of food intake and BP in wild-type mice; (2) effects of light-phase time-restricted feeding (TRF, food only available during light-phase) on BP circadian rhythm in wild-type and diabetic db/db mice; (3) the roles of the autonomic system and clock gene in light-phase TRF induced changes in BP circadian rhythm. Food intake and BP of C57BL/6J and db/db mice were simultaneously and continuously recorded using BioDAQ and telemetry systems under ad libitum or light-phase TRF. Per2 protein daily oscillation was recorded in vivo by IVIS spectrum in mPer2 Luc mice. Autonomic nerve activity was evaluated by heart rate variability, baroreflex, urinary norepinephrine (NE) and epinephrine (Epi) excretion, and mRNA expressions of catecholamines biosynthetic and catabolic enzymes, and alpha-adrenergic receptors in mesenteric resistance arteries. We found that in wild-type mice, the BP level was correlated with the food intake temporally across the 24 h. Reversing the feeding time by imposing light-phase TRF resulted in reverse or inverted BP dipping. Interestingly, the net changes in food intake were correlated with the net alteration in BP temporally under light-phase TRF. In db/db mice, light-phase TRF worsened the existing non-dipping BP. The food intake and BP circadian rhythm changes were associated with alterations in Per2 protein daily oscillation and the time-of-day variations in heart rate variability, baroreflex, and urinary excretion of NE and Epi, and increased mRNA expression of Slc6a2 (encoding NE transporter) and Adra1d (encoding alpha-adrenergic receptor 1d) in the mesenteric resistance arteries, indicating the sympathetic nervous system (SNS) was modulated after light-phase TRF. Collectively, our results demonstrated that light-phase TRF results in reverse dipping of BP in wild-type and diabetic db/db mice and revealed the potential role of the sympathetic pathway in light-phase TRF-induced BP circadian rhythm alteration.

6.
Proc Natl Acad Sci U S A ; 118(25)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34161259

RESUMO

The quantity and quality of food intake have been considered crucial for peoples' wellness. Only recently has it become appreciated that the timing of food intake is also critical. Nondipping blood pressure (BP) is prevalent in diabetic patients and is associated with increased cardiovascular events. However, the causes and mechanisms of nondipping BP in diabetes are not fully understood. Here, we report that food intake and BP were arrhythmic in diabetic db/db mice fed a normal chow diet ad libitum. Imposing a food intake diurnal rhythm by time-restricted feeding (TRF; food was only available for 8 h during the active phase) prevented db/db mice from developing nondipping BP and effectively restored the already disrupted BP circadian rhythm in db/db mice. Interestingly, increasing the time of food availability from 8 h to 12 h during the active dark phase in db/db mice prompted isocaloric feeding and still provided robust protection of the BP circadian rhythm in db/db mice. In contrast, neither 8-h nor 12-h TRF affected BP dipping in wild-type mice. Mechanistically, we demonstrate that TRF protects the BP circadian rhythm in db/db mice via suppressing the sympathetic activity during the light phase when they are inactive and fasting. Collectively, these data reveal a potentially pivotal role of the timing of food intake in the prevention and treatment of nondipping BP in diabetes.


Assuntos
Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Jejum/fisiologia , Animais , Ingestão de Energia , Camundongos , Sistema Nervoso Simpático/fisiopatologia , Fatores de Tempo
7.
Curr Opin Pharmacol ; 57: 125-131, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33721615

RESUMO

The intrinsic vascular smooth muscle contraction and vasoconstriction show time-of-day variations, contributing to the blood pressure circadian rhythm, which is essential for cardiovascular health. This brief review provides an overview of our current understanding of the mechanisms underlying the time-of-day variations of vascular smooth muscle contraction. We discuss the potential contribution of the time-of-day variations of vasoconstriction to the physiological blood pressure circadian rhythm. Finally, we survey the data obtained in the type 2 diabetic db/db mouse model that demonstrate the alterations of the time-of-day variations of vasoconstriction and the nondipping blood pressure in diabetes.


Assuntos
Diabetes Mellitus , Vasoconstrição , Animais , Pressão Sanguínea , Ritmo Circadiano , Camundongos
8.
Cell Metab ; 32(1): 44-55.e6, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32402267

RESUMO

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.


Assuntos
Envelhecimento/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Inflamação/metabolismo , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Adulto , Envelhecimento/metabolismo , Humanos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo
10.
Front Neurosci ; 13: 969, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31619950

RESUMO

People with diabetes are more likely to experience sleep disturbance than those without. Sleep disturbance can cause daytime sleepiness in diabetic patients, which may impair their daytime performance or even lead to workplace injuries. Therefore, restoring the normal sleep-wake cycle is critical for diabetic patients who experience daytime sleepiness. Previous data on a diabetic mouse model, the db/db mice, have demonstrated that the total sleep time and sleep fragmentation are increased and the daily rhythm of the sleep-wake cycle is attenuated. Accumulating evidence has shown that active time-restricted feeding (ATRF), in which the timing of food availability is restricted to the active-phase, is beneficial to metabolic health. However, it is unknown whether ATRF restores the normal sleep-wake cycle in diabetes. To test that, we used a non-invasive piezoelectric system to monitor the sleep-wake profile in the db/db mice with ad libitum feeding (ALF) as a baseline and then followed with ATRF. The results showed that at baseline, db/db mice exhibited abnormal sleep-wake patterns: the sleep time percent during the light-phase was decreased, while during the dark-phase it was increased with unusual cycling compared to control mice. In addition, the sleep bout length during both the light-phase and the full 24-h period was shortened in db/db mice. Analysis of the sleep-wake circadian rhythm showed that ATRF effectively restored the circadian but suppressed the ultradian oscillations of the sleep-wake cycle in the db/db mice. In conclusion, ATRF may serve as a novel strategy for treating diabetes-induced irregularity of the sleep-wake cycle.

11.
Mol Cell Biol ; 39(11)2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936247

RESUMO

Vasodilatory shock in sepsis is caused by the failure of the vasculature to respond to vasopressors, which results in hypotension, multiorgan failure, and ultimately patient death. Recently, it was reported that CPI-17, a key player in the regulation of smooth muscle contraction, was downregulated by lipopolysaccharide (LPS) in mesenteric arteries concordant with vascular hypocontractilty. While Sp1 has been shown to activate CPI-17 transcription, it is unknown whether Sp1 is involved in LPS-induced smooth muscle CPI-17 downregulation. Here we report that tumor necrosis factor (TNF) was critical for LPS-induced smooth muscle CPI-17 downregulation. Mechanistically, we identified two GC boxes as a key TNF response element in the CPI-17 promoter and demonstrated that KLF4 was upregulated by TNF, competed with Sp1 for the binding to the GC boxes in the CPI-17 promoter, and repressed CPI-17 transcription through histone deacetylases (HDACs). Moreover, genetic deletion of TNF or pharmacological inhibition of HDACs protected mice from LPS-induced smooth muscle CPI-17 downregulation, vascular hypocontractility, hypotension, and mortality. In summary, these data provide a novel mechanism of the transcriptional control of CPI-17 in vascular smooth muscle cells under inflammatory conditions and suggest a new potential therapeutic strategy for the treatment of vasodilatory shock in sepsis.


Assuntos
Hipotensão/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lipopolissacarídeos/metabolismo , Proteínas Musculares/genética , Músculo Liso Vascular/citologia , Fator de Transcrição Sp1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo , Técnicas de Inativação de Genes , Humanos , Hipotensão/metabolismo , Fator 4 Semelhante a Kruppel , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética
12.
J Biol Rhythms ; 34(1): 51-68, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30278816

RESUMO

Diabetic patients have an increased prevalence of blood pressure (BP) circadian rhythm disruption, which is associated with an increased risk of target organ damage and detrimental cardiovascular events. Limited information is available regarding the role of clock genes in the disruption of BP circadian rhythm in diabetes due to the lack of a diabetic animal model that allows real-time monitoring of clock gene oscillation. Here, we generated a novel diabetic db/db-mPer2Luc mouse model by crossing type 2 diabetic db/db mice with mPer2Luc knock-in mice. The daily rhythms of BP, heart rate, locomotor activity, and food and water intake were acquired by radiotelemetry or using metabolic chambers. The daily oscillation of mPer2 bioluminescence was recorded by LumiCycle in real-time in tissue explants and using the IVIS system in vivo. Our results show that db/db-mPer2Luc mice are obese, diabetic, and glucose intolerant. The db/db-mPer2Luc mice displayed a compromised BP daily rhythm, which was associated with disrupted daily rhythms in baroreflex sensitivity, locomotor activity, and metabolism, but not heart rate or food and water intake. The phase of the mPer2 daily oscillation was advanced to different extents in the explanted peripheral tissues from db/db-mPer2Luc mice relative to control mice. In contrast, no phase shift was detected in mPer2 daily oscillations in the explanted SCN. Moreover, advanced phase shift of the mPer2 daily oscillation was detected in the liver, kidney and submandibular gland in vivo of db/db-mPer2Luc mice. In conclusion, the diabetic db/db-mPer2Luc mouse is a novel animal model that allows real-time monitoring of mPer2 circadian rhythms ex vivo and in vivo. The results from db/db-mPer2Luc mice suggest that the desynchrony of mPer2 daily oscillation in peripheral tissues contributes to the loss of BP daily oscillation in diabetes.


Assuntos
Pressão Sanguínea , Relógios Circadianos/genética , Ritmo Circadiano , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Animais , Diabetes Mellitus Experimental/complicações , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/genética , Núcleo Supraquiasmático/fisiologia
13.
Arterioscler Thromb Vasc Biol ; 38(5): 1063-1075, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29437576

RESUMO

OBJECTIVE: Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development. APPROACH AND RESULTS: SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone plus high salt intake and (2) angiotensin II infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by deoxycorticosterone acetate-salt, and deletion of BMAL1 in SMCs selectively upregulated TIMP4 (tissue inhibitor of metalloproteinase 4) and suppressed deoxycorticosterone acetate-salt-induced MMP (matrix metalloproteinase) activation and elastin breakages. Moreover, BMAL1 bound to the Timp4 promoter and suppressed Timp4 transcription. CONCLUSIONS: These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion.


Assuntos
Fatores de Transcrição ARNTL/deficiência , Aneurisma da Aorta Abdominal/prevenção & controle , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição ARNTL/genética , Aldosterona , Angiotensina II , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Sítios de Ligação , Acetato de Desoxicorticosterona , Dilatação Patológica , Modelos Animais de Doenças , Elastina/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Regiões Promotoras Genéticas , Cloreto de Sódio na Dieta , Inibidores Teciduais de Metaloproteinases/genética , Inibidores Teciduais de Metaloproteinases/metabolismo , Transcrição Gênica , Inibidor Tecidual 4 de Metaloproteinase
14.
Methods Mol Biol ; 1614: 155-163, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28500602

RESUMO

Dysfunction of the renin-angiotensin-aldosterone system (RAAS) has been implicated in the etiologies of many cardiovascular diseases, including aortic aneurysm. In particular, the infusion of angiotensin II (Ang II) in the apolipoprotein E-deficient mice (apoE-/-) and low density lipoprotein receptor knockout mice (LDLR-/-) to induce aortic aneurysm has been extensively used in the field. In contrast, whether aldosterone (Aldo), an essential component of RAAS and a downstream effector of Ang II, is involved in aortic aneurysm is largely unknown. Here, we describe a new animal model for induction of aortic aneurysm in mice in which administration of deoxycorticosterone acetate (DOCA) and high salt or aldosterone and high salt, but not DOCA or high salt alone, to C57BL/6 male mice can potently induce aortic aneurysm formation and rupture in an age-dependent manner. This new aortic aneurysm mouse model is different from Ang II infusion mouse model and exhibits several unique features that mimic human aortic aneurysm.


Assuntos
Aneurisma Aórtico/induzido quimicamente , Modelos Animais de Doenças , Camundongos , Aldosterona , Animais , Determinação da Pressão Arterial , Acetato de Desoxicorticosterona , Infusões Parenterais , Masculino , Camundongos Endogâmicos C57BL , Mineralocorticoides/administração & dosagem , Mineralocorticoides/toxicidade , Cloreto de Sódio
15.
J Clin Invest ; 125(1): 324-36, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25485682

RESUMO

As the central pacemaker, the suprachiasmatic nucleus (SCN) has long been considered the primary regulator of blood pressure circadian rhythm; however, this dogma has been challenged by the discovery that each of the clock genes present in the SCN is also expressed and functions in peripheral tissues. The involvement and contribution of these peripheral clock genes in the circadian rhythm of blood pressure remains uncertain. Here, we demonstrate that selective deletion of the circadian clock transcriptional activator aryl hydrocarbon receptor nuclear translocator-like (Bmal1) from smooth muscle, but not from cardiomyocytes, compromised blood pressure circadian rhythm and decreased blood pressure without affecting SCN-controlled locomotor activity in murine models. In mesenteric arteries, BMAL1 bound to the promoter of and activated the transcription of Rho-kinase 2 (Rock2), and Bmal1 deletion abolished the time-of-day variations in response to agonist-induced vasoconstriction, myosin phosphorylation, and ROCK2 activation. Together, these data indicate that peripheral inputs contribute to the daily control of vasoconstriction and blood pressure and suggest that clock gene expression outside of the SCN should be further evaluated to elucidate pathogenic mechanisms of diseases involving blood pressure circadian rhythm disruption.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Ritmo Circadiano , Músculo Liso Vascular/metabolismo , Animais , Pressão Sanguínea , Indução Enzimática , Masculino , Artérias Mesentéricas/fisiologia , Camundongos Knockout , Contração Muscular , Desenvolvimento Muscular , Cadeias Leves de Miosina/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Processamento de Proteína Pós-Traducional , Vasoconstrição , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
16.
Arterioscler Thromb Vasc Biol ; 33(7): 1568-79, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23661677

RESUMO

OBJECTIVE: Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown. APPROACH AND RESULTS: We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm. CONCLUSIONS: The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.


Assuntos
Aorta/metabolismo , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Torácica/etiologia , Ruptura Aórtica/etiologia , Desoxicorticosterona , Receptores de Mineralocorticoides/metabolismo , Cloreto de Sódio na Dieta , Aldosterona/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/tratamento farmacológico , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/fisiopatologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/tratamento farmacológico , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Ruptura Aórtica/fisiopatologia , Apoptose , Pressão Sanguínea , Modelos Animais de Doenças , Elastina/metabolismo , Enalapril/administração & dosagem , Eplerenona , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Estresse Oxidativo , Receptores de Mineralocorticoides/agonistas , Espironolactona/administração & dosagem , Espironolactona/análogos & derivados , Fatores de Tempo
17.
Am J Physiol Heart Circ Physiol ; 305(1): H104-13, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23604714

RESUMO

Recent data revealed that protein kinase C-potentiated myosin phosphatase inhibitor of 17 kDa (CPI-17), a myosin phosphatase inhibitory protein preferentially expressed in smooth muscle, is upregulated/activated in several diseases but whether this CPI-17 increase plays a causal role in pathologically enhanced vascular smooth muscle contractility and blood pressure remains unclear. To address this possibility, we generated a smooth muscle-specific CPI-17 transgenic mouse model (CPI-17-Tg) and demonstrated that the CPI-17 transgene was selectively expressed in smooth muscle-enriched tissues, including mesenteric arteries. The isometric contractions in the isolated second-order branch of mesenteric artery helical strips from CPI-17-Tg mice were significantly enhanced compared with controls in response to phenylephrine, U-46619, serotonin, ANG II, high potassium, and calcium. The perfusion pressure increases in isolated perfused mesenteric vascular beds in response to norepinephrine were also enhanced in CPI-17-Tg mice. The hypercontractility was associated with increased phosphorylation of CPI-17 and 20-kDa myosin light chain under basal and stimulated conditions. Surprisingly, the protein levels of rho kinase 2 and protein kinase Cα/δ were significantly increased in CPI-17-Tg mouse mesenteric arteries. Radiotelemetry measurements demonstrated that blood pressure was significantly increased in CPI-17-Tg mice. However, no vascular remodeling was detected by morphometric analysis. Taken together, our results demonstrate that increased CPI-17 expression in smooth muscle promotes vascular smooth muscle contractility and increases blood pressure, implicating a pathological significant role of CPI-17 upregulation.


Assuntos
Pressão Sanguínea , Contração Isométrica/genética , Proteínas Musculares/metabolismo , Músculo Liso Vascular/fisiologia , Fosfoproteínas/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Angiotensina II/farmacologia , Animais , Cálcio/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Contração Isométrica/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Musculares/genética , Músculo Liso Vascular/metabolismo , Fenilefrina/farmacologia , Fosfoproteínas/genética , Potássio/farmacologia , Serotonina/farmacologia , Transcrição Gênica , Regulação para Cima , Vasoconstritores/farmacologia
18.
J Biol Chem ; 287(29): 24739-53, 2012 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-22637477

RESUMO

Whether group VIA phospholipase A(2) (iPLA(2)ß) is involved in vascular inflammation and neointima formation is largely unknown. Here, we report that iPLA(2)ß expression increases in the vascular tunica media upon carotid artery ligation and that neointima formation is suppressed by genetic deletion of iPLA(2)ß or by inhibiting its activity or expression via perivascular delivery of bromoenol lactone or of antisense oligonucleotides, respectively. To investigate whether smooth muscle-specific iPLA(2)ß is involved in neointima formation, we generated transgenic mice in which iPLA(2)ß is expressed specifically in smooth muscle cells and demonstrate that smooth muscle-specific expression of iPLA(2)ß exacerbates ligation-induced neointima formation and enhanced both production of proinflammatory cytokines and vascular infiltration by macrophages. With cultured vascular smooth muscle cell, angiotensin II, arachidonic acid, and TNF-α markedly induce increased expression of IL-6 and TNF-α mRNAs, all of which were suppressed by inhibiting iPLA(2)ß activity or expression with bromoenol lactone, antisense oligonucleotides, and genetic deletion, respectively. Similar suppression also results from genetic deletion of 12/15-lipoxygenase or inhibiting its activity with nordihydroguaiaretic acid or luteolin. Expression of iPLA(2)ß protein in cultured vascular smooth muscle cells was found to depend on the phenotypic state and to rise upon incubation with TNF-α. Our studies thus illustrate that smooth muscle cell-specific iPLA(2)ß participates in the initiation and early progression of vascular inflammation and neointima formation and suggest that iPLA(2)ß may represent a novel therapeutic target for preventing cardiovascular diseases.


Assuntos
Cálcio/metabolismo , Inflamação/metabolismo , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Neointima/imunologia , Neointima/metabolismo , Fosfolipases A2 Independentes de Cálcio/metabolismo , Angiotensina II , Animais , Western Blotting , Artérias Carótidas/imunologia , Artérias Carótidas/metabolismo , Células Cultivadas , Imuno-Histoquímica , Inflamação/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Oligonucleotídeos Antissenso , Fosfolipases A2 Independentes de Cálcio/genética , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Coelhos , Ratos , Ratos Sprague-Dawley
19.
PLoS One ; 7(2): e31850, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22363752

RESUMO

OBJECTIVES: Calcium independent group VIA phospholipase A(2) (iPLA(2)ß) is up-regulated in vascular smooth muscle cells in some diseases, but whether the up-regulated iPLA(2)ß affects vascular morphology and blood pressure is unknown. The current study addresses this question by evaluating the basal- and angiotensin II infusion-induced vascular remodeling and hypertension in smooth muscle specific iPLA(2)ß transgenic (iPLA(2)ß-Tg) mice. METHOD AND RESULTS: Blood pressure was monitored by radiotelemetry and vascular remodeling was assessed by morphologic analysis. We found that the angiotensin II-induced increase in diastolic pressure was significantly higher in iPLA(2)ß-Tg than iPLA(2)ß-Wt mice, whereas, the basal blood pressure was not significantly different. The media thickness and media∶lumen ratio of the mesenteric arteries were significantly increased in angiotensin II-infused iPLA(2)ß-Tg mice. Analysis revealed no difference in vascular smooth muscle cell proliferation. In contrast, adenovirus-mediated iPLA(2)ß overexpression in cultured vascular smooth muscle cells promoted angiotensin II-induced [(3)H]-leucine incorporation, indicating enhanced hypertrophy. Moreover, angiotensin II infusion-induced c-Jun phosphorylation in vascular smooth muscle cells overexpressing iPLA2ß to higher levels, which was abolished by inhibition of 12/15 lipoxygenase. In addition, we found that angiotensin II up-regulated the endogenous iPLA(2)ß protein in-vitro and in-vivo. CONCLUSION: The present study reports that iPLA(2)ß up-regulation exacerbates angiotensin II-induced vascular smooth muscle cell hypertrophy, vascular remodeling and hypertension via the 12/15 lipoxygenase and c-Jun pathways.


Assuntos
Angiotensina II/farmacologia , Fosfolipases A2 do Grupo VI/metabolismo , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/fisiopatologia , Angiotensina II/administração & dosagem , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Araquidonato 15-Lipoxigenase , Ácido Araquidônico/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diástole/efeitos dos fármacos , Hipertensão/patologia , Hipertrofia , Leucina/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Especificidade de Órgãos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Am J Physiol Heart Circ Physiol ; 302(3): H621-33, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22140039

RESUMO

This study was designed to determine whether the 24-h rhythms of clock gene expression and vascular smooth muscle (VSM) contractile responses are altered in type 2 diabetic db/db mice. Control and db/db mice were euthanized at 6-h intervals throughout the day. The aorta, mesenteric arteries, heart, kidney, and brain were isolated. Clock and target gene mRNA levels were determined by either real-time PCR or in situ hybridization. Isometric contractions were measured in isolated aortic helical strips, and pressor responses to an intravenous injection of vasoconstrictors were determined in vivo using radiotelemetry. We found that the 24-h mRNA rhythms of the following genes were suppressed in db/db mice compared with control mice: the clock genes period homolog 1/2 (Per1/2) and cryptochrome 1/2 (Cry1/2) and their target genes D site albumin promoter-binding protein (Dbp) and peroxisome proliferator-activated receptor-γ (Pparg) in the aorta and mesenteric arteries; Dbp in the heart; Per1, nuclear receptor subfamily 1, group D, member 1 (Rev-erba), and Dbp in the kidney; and Per1 in the suprachiasmatic nucleus. The 24-h contractile variations in response to phenylephrine (α(1)-agonist), ANG II, and high K(+) were significantly altered in the aortas from db/db mice compared with control mice. The diurnal variations of the in vivo pressor responses to phenylephrine and ANG II were lost in db/db mice. Moreover, the 24-h mRNA rhythms of the contraction-related proteins Rho kinase 1/2, PKC-potentiated phosphatase inhibitory protein of 17 kDa, calponin-3, tropomyosin-1/2, and smooth muscle protein 22-α were suppressed in db/db mice compared with control mice. Together, our data demonstrated that the 24-h rhythms of clock gene mRNA, mRNA levels of several contraction-related proteins, and VSM contraction were disrupted in db/db mice, which may contribute to the disruption of their blood pressure circadian rhythm.


Assuntos
Criptocromos/genética , Diabetes Mellitus Tipo 2/genética , Músculo Liso Vascular/fisiologia , Proteínas Circadianas Period/genética , Animais , Aorta/fisiologia , Pressão Sanguínea/genética , Ritmo Circadiano/genética , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Expressão Gênica/fisiologia , Coração/fisiologia , Rim/fisiologia , Masculino , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , PPAR gama/genética , Núcleo Supraquiasmático/fisiologia , Fatores de Transcrição/genética , Vasoconstrição/genética
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