Triglyceride-Glucose Index Associated with Future Renal Function Decline in the General Population.

BACKGROUND: The triglyceride-glucose index (TyG index), calculated as the logarithmic product of fasting triglyceride and glucose concentrations, is recognized as a simple marker of insulin resistance. However, the association between the TyG index and future decline of renal function remains unclear in the general population. OBJECTIVE: To investigate whether the TyG index was associated with future decline of renal function in the general population who had not progressed to chronic kidney disease stage G2. DESIGN: Retrospective longitudinal observational cohort study. PARTICIPANTS: Individuals who received a population-based health checkup at JA Ehime Kouseiren Checkup Center from 2010 to 2019 (n = 134,007). Individuals without data of baseline fasting triglyceride or glucose levels, or baseline and follow-up data of estimated glomerular filtration rate (eGFR), or those with baseline eGFR < 60 mL/min/1.73 m2 were excluded. MAIN MEASURES: Future renal function decline, defined as a ≥ 25% decrease in eGFR from baseline. KEY RESULTS: Of 10,758 participants, 8,076 were classified into the low TyG index group (TyG index < 8.76, 1st to 3rd quartiles) and 2,682 into the high TyG index group (TyG index ≥ 8.76, 4th quartile). The mean follow-up period was 37.8 ± 23.6 months. The incidence rates of renal function decline were 0.31 and 0.69 per 100 person-years in the low and high TyG index groups, respectively. In multivariate Cox proportional hazard models, high TyG index was significantly associated with future renal function decline (hazard ratio 2.25, 95% CI 1.40-3.60). This association was consistent across subgroups stratified by age, sex, body mass index, baseline eGFR, and diagnosed hypertension, diabetes, or dyslipidemia. CONCLUSION: In the general population, high TyG index was associated with future renal function decline. The TyG index may be useful in identifying individuals at high risk for future renal function decline in the setting of health checkups.

Lack of ATP2B1 in CD4+ T Cells Causes Colitis.

BACKGROUND: The ATP2B1 gene encodes for a calcium pump, which plays a role in removing Ca2+ from cells and maintaining intracellular Ca2+ homeostasis. Reduction of the intracellular Ca2+ concentration in CD4+ T cells is thought to reduce the severity of colitis, while elevation of Ca2+ in CD4+ T cells induces T cell hyperactivity. Our aim was to clarify the role of ATP2B1 in CD4+ T cells and in inflammatory bowel disease development. METHODS: A murine CD4+ T cell-specific knockout (KO) of ATP2B1 was created using a Cre-loxP system. CD4+ T cells were isolated from thymus, spleen, and blood using fluorescence-activated cell sorting. To quantify messenger RNA levels, quantitative real-time polymerase chain reaction was performed. RESULTS: Although the percentages of CD4+ T cells in both KO mouse spleen and blood decreased compared with those of the control samples, both T-bet (a T helper 1 [Th1] activity marker) and GATA3 (a Th2 activity marker) expression levels were further increased in KO mouse blood CD4+ T cells (vs control blood). Diarrhea and colonic wall thickening (with mucosal changes, including crypt distortion) were seen in KO mice but not in control mice. Prior to diarrhea onset, the KO mouse colon length was already noted to be shorter, and the KO mouse stool water and lipid content were higher than that of the control mice. Tumor necrosis factor α and gp91 expressions were increased in KO mouse colon. CONCLUSIONS: Lack of ATP2B1 in CD4+ T cells leads to Th1 and Th2 activation, which contributes to colitis via elevation of tumor necrosis factor α and oxidative stress.

ATP2B1 deficiency in CD4+ T cells leads to T helper 1/T helper 2 activation, which in turn increases tumor necrosis factor α and oxidative stress. These changes contribute to colitis, which is characterized by diarrhea and colonic wall thickening.

Association of baseline electrocardiographic left ventricular hypertrophy with future renal function decline in the general population.

Electrocardiographic left ventricular hypertrophy (LVH) could predict adverse renal outcomes in patients with hypertension. This study aimed to investigate the association between electrocardiographic LVH and future decline in renal function in the general population using a dataset of population-based health checkups from 2010 to 2019 including 19,825 participants. Electrocardiographic LVH was defined according to the Minnesota code. Renal function decline was defined as a decrease of ≥ 25% in the estimated glomerular filtration rate from baseline to < 60 mL/min/1.73 m2. Electrocardiographic LVH was found in 1263 participants at the baseline visit. The mean follow-up period was 3.4 ± 1.9 years. The incidence rates of renal function decline were 0.30 and 0.78 per 100 person-years in the non-LVH group and LVH groups, respectively. Electrocardiographic LVH was associated with the risk for renal function decline in the adjusted analysis (hazard ratio 1.69, 95% confidence interval 1.14-2.50, P = 0.009). This association was comparable across subgroups stratified by age, sex, body mass index, diagnosed hypertension, systolic blood pressure, hemoglobin A1c, and urinary protein. This study underscores the usefulness of electrocardiographic LVH to detect high-risk individuals for renal function decline in the setting of health checkups in the general population.

Message to researchers: the characteristic absence of a posterior communicating artery is easily lost in the gerbil.

The Mongolian gerbil has historically been useful for brain ischemia experiments, owing to the gerbil's uniquely underdeveloped circle of Willis (CoW). This led to a gerbil model of cochlear ischemia being generated in our unit. However, we have found that the usual severe hearing loss seen in this model was not being induced consistently in recent experiments using the MON/Jms/GbsSlc gerbil (the sole commercially available gerbil in Japan). We set out to evaluate the posterior communicating artery (PcomA) in MON/Jms/GbsSlc, to re-establish whether this strain is appropriate for ischemia models. Having found that this unique feature is often lost, we then attempted to breed for the characteristic absent PcomA. India-ink perfusion revealed that the percentage of intact bilateral PcomA ("communicating type") in the MON/Jms/GbsSlc gerbil was 57%; unilateral only ("unilateral communicating type") was 39%; and completely absent PcomA ("non-communicating type") was 4%. We were able to obtain few examples of the indigenous old aged Japanese UNG/Mz gerbil strain (at University of Miyazaki). Unfortunately, the pure UNG/Mz female was too elderly for mating. Therefore, selective breeding crosses between MON/Jms/GbsSlc and male UNG/Mz were carried out. After five generations of selective breeding, the percentage of non-communicating type gerbils was significantly higher in the newly generated strain, MON/Jms/SlcMz (F6 generation; 63%) than in the MON/Jms/GbsSlc gerbil. Bilateral common carotid artery occlusion surgery demonstrated that the cerebral blood flow was significantly reduced in MON/Jms/SlcMz compared with MON/Jms/GbsSlc (p < 0.0001) and induced more hippocampal injuries in MON/Jms/SlcMz than in MON/Jms/GbsSlc (p < 0.01). In conclusion, the commercially available MON/Jms/GbsSlc gerbil can easily regain PcomA, and we established a new gerbil strain (MON/Jms/SlcMz) displaying non-PcomA.

E-cigarette exposure augments murine abdominal aortic aneurysm development: role of Chil1.

AIMS: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown. METHODS AND RESULTS: We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signalling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model. CONCLUSIONS: In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further, we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.

Genetic Manipulation of Calcium Release-Activated Calcium Channel 1 Modulates the Multipotency of Human Cartilage-Derived Mesenchymal Stem Cells.

Calcium is a ubiquitous intracellular messenger that has a crucial role in determining the proliferation, differentiation, and functions of multipotent mesenchymal stem cells (MSCs). Our study is aimed at elucidating the influence of genetically manipulating Ca2+ release-activated Ca2+ (CRAC) channel-mediated intercellular Ca2+ signaling on the multipotency of MSCs. The abilities of genetically engineered MSCs, including CRAC-overexpressing and CRAC-knockout MSCs, to differentiate into multiple mesenchymal lineages, including adipogenic, osteogenic, and chondrogenic lineages, were evaluated. CRAC channel-mediated Ca2+ influx into these cells was regulated, and the differentiation fate of MSCs was modified. Upregulation of intracellular Ca2+ signals attenuated the adipogenic differentiation ability and slightly increased the osteogenic differentiation potency of MSCs, whereas downregulation of CRACM1 expression promoted chondrogenic differentiation potency. The findings demonstrated the effects of genetically manipulating MSCs by targeting CRACM1. CRAC-modified MSCs had distinct differentiation fates to adipocytes, osteoblasts, and chondrocytes. To aid in the clinical implementation of tissue engineering strategies for joint regeneration, these data may allow us to identify prospective factors for effective treatments and could maximize the therapeutic potential of MSC-based transplantation.

Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation-Implications for Abdominal Aortic Aneurysm Susceptibility.

Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness. Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed. Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening. Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery.

Systemic Upregulation of IL-10 (Interleukin-10) Using a Nonimmunogenic Vector Reduces Growth and Rate of Dissecting Abdominal Aortic Aneurysm.

Objective- Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results- Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE-/- infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.1±10.8% (control) to 131.0±5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4+/CD25+/Foxp3 (forkhead box P3)+ regulatory T cells, with fewer CD8+/GZMB+ (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF-α (tumor necrosis factor-α), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions- Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.

MicroRNA-Mediated Therapy Modulating Blood-Brain Barrier Disruption Improves Vascular Cognitive Impairment.

OBJECTIVE: There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood-brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood-brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment. APPROACH AND RESULTS: Using a mouse model of vascular cognitive impairment, chronic cerebral hypoperfusion within the white matter was induced with bilateral common carotid artery stenosis (BCAS) surgery. TNFα gene expression was increased in white matter post-BCAS surgery, and TNFα stimulation decreased claudin-5, ZO-1 (tight-junction protein 1), and occludin gene expression in murine brain endothelial cells. In silico analysis predicted 8 candidate microRNAs as regulators of claudin-5, ZO-1, and occludin gene expression. Of these, only miR-501-3p was upregulated by TNFα in vitro and was upregulated in the white matter after BCAS surgery. Further, miR-501-3p directly bound to the 3'-untranslated region of human ZO-1 and downregulated transendothelial electric resistance. In vivo administration of a locked nucleic acid -modified antisense oligonucleotide versus miR-501-3p suppressed BCAS-induced reduction of ZO-1 gene expression and blood-brain barrier disruption within the white matter and significantly ameliorated working memory deficits after BCAS surgery. CONCLUSIONS: We here provide the first evidence that the TNFα-miR-501-3p-ZO-1 axis plays an important role in the pathogenesis of cerebral hypoperfusion-induced working memory deficits and white matter lesions, as a result of blood-brain barrier breakdown via tight junction disruption. Therapeutic manipulation of miR-501-3p holds promise for limiting vascular cognitive impairment progression.

Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus.

RATIONALE: Accelerated arterial stiffening is a major complication of diabetes mellitus with no specific therapy available to date. OBJECTIVE: The present study investigates the role of the osteogenic transcription factor runt-related transcription factor 2 (Runx2) as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes mellitus. METHODS AND RESULTS: Using a murine model of type 2 diabetes mellitus (db/db mice), we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae, as well as in thoracic aortic samples from patients with type 2 diabetes mellitus. Vascular smooth muscle cell-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that expression of Runx2 in diabetes mellitus is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter. CONCLUSIONS: In conclusion, this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes mellitus, promoting arterial stiffness irrespective of calcification.

ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice.

Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density, and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment.

Rosuvastatin ameliorates early brain injury after subarachnoid hemorrhage via suppression of superoxide formation and nuclear factor-kappa B activation in rats.

BACKGROUND: Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been suggested to possess pleiotropic effects, including antioxidant and anti-inflammatory properties. We investigated the protective effects of pretreatment with rosuvastatin, a relatively hydrophilic statin, on early brain injury (EBI) after a subarachnoid hemorrhage (SAH), using the endovascular perforation SAH model. METHODS: Eighty-six male Sprague-Dawley rats were randomly divided into 3 groups: (1) sham operation, (2) SAH+vehicle, and (3) SAH+10 mg/kg rosuvastatin. Rosuvastatin or vehicle was orally administered to rats once daily from 7 days before to 1 day after the SAH operation. After SAH, we examined the effects of rosuvastatin on the neurologic score, brain water content, neuronal cell death estimated by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate nick end labeling staining, blood-brain barrier disruption by immunoglobulin G (IgG) extravasation, oxidative stress, and proinflammatory molecules. RESULTS: Compared with the vehicle group, rosuvastatin significantly improved the neurologic score and reduced the brain water content, neuronal cell death, and IgG extravasation. Rosuvastatin inhibited brain superoxide production, nuclear factor-kappa B (NF-κB) activation, and the increase in activated microglial cells after SAH. The increased expressions of tumor necrosis factor-alpha, endothelial matrix metalloproteinase-9, and neuronal cyclooxygenase-2 induced by SAH were prevented by rosuvastatin pretreatment. CONCLUSIONS: The present study demonstrates that rosuvastatin pretreatment ameliorates EBI after SAH through the attenuation of oxidative stress and NF-κB-mediated inflammation.

Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion.

OBJECTIVE: There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions. APPROACH AND RESULTS: A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1(-/-)) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1(-/-) mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1(-/-) mice. Cerebral nitrotyrosine was increased in wild-type and ASK1(-/-) BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1(-/-) mice. CONCLUSIONS: Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood-brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment.

Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation.

This study aimed to examine the potential protective effect of rosuvastatin against cerebral ischemia/reperfusion injury and its mechanisms. Forty-eight male SD rats underwent 90 min of transient middle cerebral artery occlusion (tMCAO), followed by reperfusion. Rats were orally given (1) rosuvastatin 1mg/kg, (2) rosuvastatin 10mg/kg or (3) water (vehicle) once a day from 7 days before to 1 day after induction of tMCAO. Neurological score, infarct volume, and oxidative stress-related molecules (assessed by immunohistochemistry, dihydroethidium staining, or western blotting) were estimated at 24h after reperfusion. Rosuvastatin prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The increases in activated microglia, macrophage, and superoxide levels usually caused by ischemia/reperfusion were significantly ameliorated by rosuvastatin. Rosuvastatin also inhibited the upregulation of gp91(phox) and p22phox, phosphorylation of nuclear factor-kappa B, and induction of cyclooxygenase 2 and inducible nitric oxide synthase, compared with vehicle. The results suggest that pretreatment with rosuvastatin may be a promising therapeutic strategy for cerebral ischemia/reperfusion injury, through attenuation of oxidative stress and inflammation.

Amlodipine enhances amelioration of vascular insulin resistance, oxidative stress, and metabolic disorders by candesartan in metabolic syndrome rats.

BACKGROUND: The pharmacological advantage of combination of an angiotensin receptor blocker (ARB) and a calcium-channel blocker (CCB) is not fully defined. This study was undertaken to elucidate the potential benefit of their combination in metabolic syndrome. METHODS: SHR/NDmcr-cp (SHRcp), a rat model of human metabolic syndrome, were divided into four groups, and were administered (i) vehicle, (ii) candesartan (an ARB) 0.3 mg/kg/day, (iii) amlodipine (a CCB) 3 mg/kg/day, and (iv) candesartan 0.3 mg/kg/day plus amlodipine 3 mg/kg/day, for 4 weeks. RESULTS: Candesartan, amlodipine, or their combination significantly ameliorated the impairment of vascular endothelium-dependent relaxation with acetylcholine in SHRcp. However, the impairment of insulin-induced vasodilation in SHRcp was partially improved by candesartan alone, but not by amlodipine alone. Interestingly, amlodipine added to candesartan synergistically enhanced the improvement of impaired insulin-induced vasodilation by candesartan, indicating the synergistic improvement of vascular insulin resistance by the combination of these drugs. Candesartan alone, but not amlodipine alone, significantly attenuated vascular superoxide and NADPH oxidase subunit p22phox in SHRcp. Amlodipine added to candesartan synergistically enhanced the reduction of vascular p22phox levels and superoxide by candesartan in SHRcp, suggesting the association of vascular insulin resistance with oxidative stress. Furthermore, the combination of candesartan with amlodipine synergistically decreased the increase in visceral adipocyte size, serum free-fatty acid, and tumor necrosis factor-α in SHRcp. CONCLUSIONS: ARB and CCB combination synergistically ameliorated vascular insulin resistance in metabolic syndrome, being associated with the synergistic attenuation of vascular oxidative stress and metabolic disorders.

Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF.

This study was undertaken to elucidate a novel mechanism underlying angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or heart failure, were orally given irbesartan (an AT1 receptor blocker), tempol (a superoxide dismutase mimetic) or hydralazine (a vasodilator). Irbesartan significantly ameliorated left ventricular ischemia and prevented the development of cardiac hypertrophy and fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant cardiac hypertrophy and fibrosis displayed decreased myocardial vascular endothelial growth factor (VEGF) expression and increased cardiac apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with irbesartan significantly reversed these phenotypes. Tempol treatment of DS rats mimicked all the above-mentioned effects of irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in angiotensin II-induced progression of cardiac injury.

Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-γ-dependent activity.

Experimental and clinical data support the notion that peroxisome proliferator-activated receptor γ (PPARγ) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPARγ agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPARγ activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPARγ antagonist), and losartan with no PPARγ activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NFκB) activation and tumor necrosis factor α. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPARγ activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPARγ in db/db mice and this effect of telmisartan was cancelled by the coadministration of GW9662. Our data provided the first evidence indicating that PPARγ activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. PPARγ activity of telmisartan was involved in the normalization of vascular PPARγ downregulation in diabetic mice. Thus, telmisartan seems to exert vascular protective effects in hypertensive patients with diabetes.

Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease.

BACKGROUND: Coenzyme Q10 levels are low in patients with coronary artery disease (CAD), and increasing or preserving coenzyme Q10 could be a beneficial strategy. Exercise and statins improve high-density lipoprotein cholesterol (HDL-C) levels. However, statins inhibit coenzyme Q10 biosynthesis, and the combination of statins with coenzyme Q10 supplementation increases HDL-C compared to statins alone. We compared the effects of two statins (rosuvastatin and atorvastatin) combined with exercise on coenzyme Q10 and HDL-C levels in CAD patients. METHODS: After randomizing 28 CAD patients to rosuvastatin (n=14) and atorvastatin (n=14) groups, patients performed weekly in-hospital aerobic exercise and daily home exercise for 20 weeks. We measured serum lipids, ubiquinol, and exercise capacity. RESULTS: Both statins equally improved exercise capacity and lowered low-density lipoprotein cholesterol and triglyceride levels. Rosuvastatin significantly increased HDL-C (rosuvastatin, +12 ± 9 mg/dL [+30%], atorvastatin, +5 ± 5 mg/dL [+13%], p=0.014) and apolipoprotein A1 (ApoA1) (rosuvastatin, +28.3 ± 20.7 mg/dL, atorvastatin, +13.4 ± 12.0 mg/dL, p=0.030) compared to atorvastatin. Atorvastatin significantly decreased serum ubiquinol (731 ± 238 to 547 ± 219 nmol/L, p=0.001), but rosuvastatin (680±233 to 668 ± 299 nmol/L, p=0.834) did not. There was a significant positive correlation between changes in ubiquinol and ApoA1 (r=0.518, p=0.005). Multivariate regression analysis showed that changes in ubiquinol correlated significantly with changes in ApoA1 after adjusting for age, sex, body mass index, and smoking (ß=0.502, p=0.008). CONCLUSIONS: Compared to atorvastatin, rosuvastatin combined with exercise significantly preserved ubiquinol levels associated with an increase in HDL-C. Rosuvastatin with regular exercise could be beneficial for CAD patients.

Primary systemic amyloidosis with bloody pericardial effusion.

A 73-year-old woman was admitted due to exertional dyspnea. It was considered that a large amount of pericardial effusion caused diastolic heart failure; pericardial paracentesis showed bloody effusion. There were no findings of malignancy or other abnormal findings in the examination. Further examinations were planned but she died of ventricular tachycardia attack. Pathological autopsy revealed primary systemic amyloidosis. Pathologically it was possible that the local inflammation (epicarditis) due to the deposition of amyloid in the epicardium and perivascular tissue caused the bloody effusion. There are no reports of primary systemic amyloidosis with hemorrhagic pericardial effusion. We report this rare case with pathological consideration.