Outcomes, Symptomatology, and Mortality of Children Presenting With Bacterial Meningitis at Allied Hospitals of Rawalpindi Medical University, Pakistan: A Cross-Sectional Study.

Introduction Bacterial meningitis (BM) is a neurologic emergency mainly affecting children under the age of two. Clinical symptoms are rarely evident in children, thus making a diagnosis is a challenge. Antibiotic therapy should be started timely to ensure the avoidance of significant morbidity and mortality. This study aims to assess the outcomes, mortality, and symptomatology of children presenting with BM in allied hospitals of Rawalpindi Medical University, Pakistan. Methods It is a cross-sectional study employing a sample size of 201, conducted at the Allied Hospitals of Rawalpindi Medical University, Pakistan from a period of January 2023 to August 2023. Non-probability convenience sampling was used. Children aged between newborns and 14 years of age with a confirmed diagnosis of bacterial meningitis were included in this study. The study population was divided into five different age groups. Three different outcomes were studied including complete recovery, development of complications, and death. Data was entered into and analyzed by Statistical Package for the Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY, USA). Descriptive statistics were applied to the demographic data. The chi-square analytical test was applied to study the association between the categorical variables. Results One hundred nineteen (59.2%) of the study's population were males. One hundred twenty-six (62.7%) of the patients were born through a spontaneous vaginal delivery (SVD). The majority (54%) of the study population were infants. Twenty-three percent were newborns, 13% were toddlers, 6% were preschool children, and 4% were school-age children. The majority (85%) of the study participants belonged to lower socioeconomic backgrounds. Ninety percent of the cases had symptoms of fever, seizures, and poor feeding. Neck stiffness was significantly associated with death as an outcome (p-value=0.01). The overall mortality amongst the study population was 20%. Forty-nine percent of the study population recovered completely, whereas 31% had complications following the diagnosis. Neonates had a higher mortality rate than infants (45% vs 9% respectively). Conclusion The most common presenting symptoms were fever, vomiting, seizures, and neck stiffness. Poor feeding was also seen in most cases. The rate of complications and death is observed to be relatively higher following the diagnosis of bacterial meningitis as compared to rates in the surrounding and developed countries. Out of all signs and symptoms, the presence of neck stiffness was significantly associated with death as an outcome among children with bacterial meningitis.

Improving the Quality and Completeness of Discharge Summaries at a Tertiary Care Hospital in Pakistan: A Quality Improvement Project.

Introduction Discharge summaries (DS) allow continued patient care after being discharged from the hospital. Only a few quality improvement projects (QIPs) focused on assessing and improving the quality and completeness of DS at tertiary care hospitals have been undertaken in Pakistan. This QIP aimed to evaluate and enhance the quality and completeness of DS at a tertiary care hospital in Pakistan to facilitate seamless healthcare transitions. Methods A QIP was conducted in the medical unit of a tertiary care hospital in Rawalpindi, Pakistan. The DS were assessed using the e-discharge summary self-assessment checklist devised by the Royal College of Physicians (RCP). This QIP was done by the plan, do, study, act (PDSA) cycle. The PDSA cycle comprised two audit cycles and an intervention in between them. The first audit cycle (AC) was conducted on 150 DS. Its duration was from March 2023 to June 2023. An educational workshop was conducted before the re-audit cycle (RAC) to address deficiencies and reinforce the implementation of the guidelines provided by the RCP. The RAC was conducted from June 2023 to August 2023. 100 DS were studied and analyzed to assess for improvement in the completeness of DS. Frequencies and percentages were calculated in each audit cycle. The Chi-squared test was applied to compare the statistical difference between the results of both audit cycles. Results A total of 150 DS were analyzed in the first AC and 100 DS in the RAC. The results of the first AC show that the details of any allergies were recorded only in 3% of the DS; this percentage significantly improved to 51% after the RAC (p-value <0.05). Relevant past medical history was included in 52% and 88% of the DS during the first AC and RAC, respectively (p-value <0.05). Secondary diagnoses were written in 54% and 71% of the DS during the first AC and RAC, respectively (p-value <0.05). Details of relevant investigations were included in 60% and 88% of the DS during the first AC and RAC, respectively (p-value <0.05). The post-discharge management plan was written in 90% and 98% of the DS during the first AC and RAC, respectively (p-value <0.05). The follow-up plan was written clearly in 65% and 93% of the DS during the first AC and RAC, respectively (p-value <0.05).  Conclusion The DS was found to be incomplete after analyzing the results of the first AC. The details related to allergies, medications, operations, and procedures were found to be missing in the majority of the cases. No mention of the patient's concerns or expectations was made in the DS. The results of the RAC showed improvement in the level of completeness of DS. The majority of the weak points observed after the first AC seemed to have improved after the RAC, which shows that intervention proved to be quite effective in improving the completeness and quality of DS. The RAC showed significant improvement in the completeness of the details relating to investigations, allergies, past medical history, secondary diagnoses, and the post-discharge follow-up plan. QIP must be routinely carried out to assess and improve the completeness and quality of DS at hospitals.

Influence of an atomistic protrusion at the tip apex on enhancing molecular emission in tunnel junctions: A theoretical study.

Light emission from the gap of a scanning tunneling microscope can be used to investigate many optoelectronic processes at the single-molecule level and to gain insight into the fundamental photophysical mechanisms involved. One important issue is how to improve the quantum efficiency of quantum emitters in the nanometer-sized metallic gap so that molecule-specific emission can be clearly observed. Here, using electromagnetic simulations, we systematically investigate the influence of an atomic-scale protrusion at the tip apex on the emission properties of a point dipole in the plasmonic nanocavity. We found that such an atomistic protrusion can induce strong and spatially highly confined electric fields, thus increasing the quantum efficiency of molecular fluorescence over two orders of magnitude even when its dipole is oriented parallel to the metal surface, a situation occurring in most realistic single-molecule electroluminescence experiments. In addition, our theoretical simulations indicate that due to the lightning rod effect induced by the protrusion in a plasmonic nanocavity, the quantum efficiency increases monotonically as the tip approaches the dipole to the point of contact, instead of being quenched, thus explaining previous experimental observations with ever-enhancing fluorescence. Furthermore, we also examine in detail how the protrusion radius, height, and material affect the protrusion-induced emission enhancement. These results are believed to be instructive for further studies on the optoelectronic properties of single molecules in tip-based plasmonic nanocavities.

BET Protein-Mediated Transcriptional Regulation in Heart Failure.

Heart failure is a complex disease process with underlying aberrations in neurohormonal systems that promote dysregulated cellular signaling and gene transcription. Over the past 10 years, the advent of small-molecule inhibitors that target transcriptional machinery has demonstrated the importance of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in regulating gene transcription in multiple mouse models of cardiomyopathy. BETs bind to acetylated histone tails and transcription factors to integrate disparate stress signaling networks into a defined gene expression program. Under myocardial stress, BRD4, a BET family member, is recruited to superenhancers and promoter regions of inflammatory and profibrotic genes to promote transcription elongation. Whole-transcriptome analysis of BET-dependent gene networks suggests a major role of nuclear-factor kappa b and transforming growth factor-beta in the development of cardiac fibrosis and systolic dysfunction. Recent investigations also suggest a prominent role of BRD4 in maintaining cardiomyocyte mitochondrial respiration under basal conditions. In this review, we summarize the data from preclinical heart failure studies that explore the role of BET-regulated transcriptional mechanisms and delve into landmark studies that define BET bromodomain-independent processes involved in cardiac homeostasis.

Deletion of NF-κB/RelA in Angiotensin II-Sensitive Mesenchymal Cells Blocks Aortic Vascular Inflammation and Abdominal Aortic Aneurysm Formation.

OBJECTIVE: Infusion of angiotensin II (Ang II) induces extracellular matrix remodeling and inflammation resulting in abdominal aortic aneurysms (AAAs) in normolipidemic mice. Although Ang II activates mesenchymal cells in the media and adventitia to become fibrogenic, the sentinel role of this mesenchymal population in modulating the inflammatory response and aneurysms is not known. We test the hypothesis that these fibrogenic mesenchymal cells play a critical role in Ang II-induced aortic wall vascular inflammation and AAA formation. APPROACH AND RESULTS: Ang II infusion increased phospho-Ser536-RelA and interleukin (IL)-6 immunostaining in the abdominal aorta. In addition, aortic mRNA transcripts of RelA-dependent cytokines IL-6 and IL-1ß were significantly elevated suggesting that Ang II functionally activates RelA signaling. To test the role of mesenchymal RelA in AAA formation, we generated RelA-CKO mice by administering tamoxifen to double transgenic mice harboring RelA-flox alleles and tamoxifen-inducible Col1a2 promoter-driven Cre recombinase (Col1a2-CreERT). Tamoxifen administration to Col1a2-CreERT•mT/mG mice induced Cre expression and RelA depletion in aortic smooth muscle cells and fibroblasts but not in endothelial cells. Infusion of Ang II significantly increased abdominal aortic diameter and the incidence of AAA in RelA wild-type but not in RelA-CKO mice, independent of changes in systolic blood pressure. Furthermore, mesenchymal cell-specific RelA-CKO mice exhibited decreased expression of IL-6 and IL-1ß cytokines and decreased recruitment of C68+ and F4/80lo•Ly6Chi monocytes during Ang II infusion. CONCLUSIONS: Fibrogenic mesenchymal RelA plays a causal role in Ang II-induced vascular inflammation and AAA in normolipidemic mice.

Coordinate activities of BRD4 and CDK9 in the transcriptional elongation complex are required for TGFß-induced Nox4 expression and myofibroblast transdifferentiation.

Transdifferentiation of quiescent dermal fibroblasts to secretory myofibroblasts has a central role in wound healing and pathological scar formation. This myofibroblast transdifferentiation process involves TGFß-induced de novo synthesis of alpha smooth muscle cell actin (αSMA)+ fibers that enhance contractility as well as increased expression of extracellular matrix (ECM) proteins, including collagen and fibronectin. These processes are mediated upstream by the reactive oxygen species (ROS)-producing enzyme Nox4, whose induction by TGFß is incompletely understood. In this study, we demonstrate that Nox4 is involved in αSMA+ fiber formation and collagen production in primary human dermal fibroblasts (hDFs) using a small-molecule inhibitor and siRNA-mediated silencing. Furthermore, TGFß-induced signaling via Smad3 is required for myofibroblast transformation and Nox4 upregulation. Immunoprecipitation-selected reaction monitoring (IP-SRM) assays of the activated Smad3 complex suggest that it couples with the epigenetic reader and transcription co-activator bromodomain and extraterminal (BET) domain containing protein 4 (BRD4) to promote Nox4 transcription. In addition, cyclin-dependent kinase 9 (CDK9), a component of positive transcription elongation factor, binds to BRD4 after TGFß stimulation and is also required for RNA polymerase II phosphorylation and Nox4 transcription regulation. Surprisingly, BRD4 depletion decreases myofibroblast differentiation but does not affect collagen or fibronectin expression in primary skin fibroblasts, whereas knockdown of CDK9 decreases all myofibroblast genes. We observe enhanced numbers and persistence of myofibroblast formation and TGFß signaling in hypertrophic scars. BRD4 inhibition reverses hypertrophic skin fibroblast transdifferentiation to myofibroblasts. Our data indicate that BRD4 and CDK9 have independent, coordinated roles in promoting the myofibroblast transition and suggest that inhibition of the Smad3-BRD4 pathway may be a useful strategy to limit hypertrophic scar formation after burn injury.

Generation and characterization of a novel transgenic mouse harboring conditional nuclear factor-kappa B/RelA knockout alleles.

BACKGROUND: Nuclear Factor-Kappa B (NF-kB) is a family of transcription factors that are important in embryonic development, inflammation, epithelial-to-mesenchymal transition and cancer. The 65 kDa RelA subunit is the major transcriptional activator of the NF-kB pathways. Whole-body deficiency of RelA leads to massive apoptosis of liver hepatocytes and death in utero. To study the role of RelA in physiology and in disease states in a manner that circumvents this embryonic lethal phenotype, we have generated a mouse with RelA conditional knockout (CKO) alleles containing loxP sites that are deleted by activated Cre recombinase. RESULTS: We demonstrate that RelACKO/CKO mice are fertile, do not display any developmental defects and can be crossed with Cre-expressing mice to delete RelA in a temporal, tissue-specific manner. Our mating of RelACKO/CKO mice with Zp3-Cre transgenic led to embryonic lethality of RelA-deficient embryos. In contrast, mating of RelACKO/CKO mice with Col1α2-CreER mice allowed for the generation of double transgenics which could be stimulated with tamoxifen to induce fibroblast-specific RelA deletion in adulthood. CONCLUSIONS: Based on our collective data, we conclude that this novel RelACKO/CKO mouse allows for efficient deletion of RelA in a tissue-specific manner. This RelACKO/CKO mouse will be an invaluable tool for deciphering the mechanistic roles of RelA in various cells and tissues during development and in disease.

Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation.

On April 29, 2015, Son and colleagues published an article entitled "Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma" in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus. The additional findings of increased adventitial fibrotic deposition, marked infiltration of macrophages, and increased expression of matrix metalloprotease-9 (MMP-9) and IL-6 were blocked with neutralizing GM-CSF antibodies, or recapitulated in normal mice with excess GM-CSF administration. The authors concluded that GM-CSF is a key regulatory molecule in the development of AAA and further suggested that activation of GM-CSF is independent of the transforming growth factor ß (TGFß)-Smad pathway associated with the Marfan aortic pathology. In this perspective, we expand on this mechanism, drawing from previous studies implicating a similar essential role for IL-6 signaling in macrophage activation, Th17 expansion and aortic dissections. We propose a sequential "two-hit" model of vascular inflammation involving initial vascular injury followed by recruitment of Ly6C(hi) macrophages. Aided by fibroblast interactions inflammatory macrophages produce amplification of IL-6 and GM-CSF expression that converge on a common, pathogenic Janus kinase (JAK)-signal transducers and activations of transcription 3 (STAT3) signaling pathway. This pathway stimulates effector functions of macrophages, promotes differentiation of Th17 lymphocytes and enhances matrix metalloproteinase expression, ultimately resulting in deterioration of vascular wall structural integrity. Further research evaluating the impact of interventions modulating this common JAK-STAT3 pathway may yield new therapeutic interventions for late stages of vascular expansion in inflammation driven aortic disease.

Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes.

Alternative splicing (AS) defects that adversely affect gene expression and function have been identified in diabetic hearts; however, the mechanisms responsible are largely unknown. Here, we show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions. RBFOX2 controls AS of genes with important roles in heart function relevant to diabetic cardiomyopathy. RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 AS activity. A dominant-negative (DN) isoform of RBFOX2 that blocks RBFOX2-mediated AS is generated in diabetic hearts. DN RBFOX2 interacts with wild-type (WT) RBFOX2, and ectopic expression of DN RBFOX2 inhibits AS of RBFOX2 targets. Notably, DN RBFOX2 expression is specific to diabetes and occurs at early stages before cardiomyopathy symptoms appear. Importantly, DN RBFOX2 expression impairs intracellular calcium release in cardiomyocytes. Our results demonstrate that RBFOX2 dysregulation by DN RBFOX2 is an early pathogenic event in diabetic hearts.

Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma.

A pathological hallmark of asthma is chronic injury and repair, producing dysfunction of the epithelial barrier function. In this setting, increased oxidative stress, growth factor- and cytokine stimulation, together with extracellular matrix contact produces transcriptional reprogramming of the epithelial cell. This process results in epithelial-mesenchymal transition (EMT), a cellular state associated with loss of epithelial polarity, expression of mesenchymal markers, enhanced mobility and extracellular matrix remodeling. As a result, the cellular biology of the EMT state produces characteristic changes seen in severe, refractory asthma: myofibroblast expansion, epithelial trans-differentiation and subepithelial fibrosis. EMT also induces profound changes in epithelial responsiveness that affects innate immune signaling that may have impact on the adaptive immune response and effectiveness of glucocorticoid therapy in severe asthma. We discuss how this complex phenotype is beginning to be understood using systems biology-level approaches through perturbations coupled with high throughput profiling and computational modeling. Understanding the distinct changes induced by EMT at the systems level may provide translational strategies to reverse the altered signaling and physiology of refractory asthma.

IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome.

BACKGROUND: Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin-6 (IL-6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin-deficient mice (mgR/mgR). METHODS AND RESULTS: MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7 ± 0.1 and 1.3 ± 0.1 for mgR/mgR versus wild-type mice, respectively; P<0.001). IL-6 signaling was increased in mgR/mgR aortas measured by increases in IL-6 and SOCS3 mRNA transcripts (P<0.05) and in cytokine secretion of IL-6, MCP-1, and GM-CSF (P<0.05). To investigate the role of IL-6 signaling, we generated mgR homozygous mice with IL-6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial-adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase-9 and had significantly reduced aortic dilation (1.0 ± 0.1 versus 1.6 ± 0.2 mm change from baseline, DKO versus mgR/mgR, P<0.05) that did not affect rupture and survival. CONCLUSION: Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.

Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice.

OBJECTIVE: Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6-signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice. APPROACH AND RESULTS: Ang II infusion induced aortic dissections and CD4(+)-interleukin 17A (IL-17A)-expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6(-/-) mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II-infused mice with IL-17A-neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A-neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription-3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II-mediated aortic dissections occurred independent of blood pressure changes. CONCLUSIONS: Our results indicate that the IL-6-signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.

Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice.

Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAA) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male low-density lipoprotein receptor-/- mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg per day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1000 ng/kg per minute) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, proinflammatory cytokines (IL-6, monocyte chemoattractant protein-1), and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycolate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in low-density lipoprotein receptor-/- mice.

Increasing proportions of tyrosine hydroxylase-immunoreactive interneurons colocalize with choline acetyltransferase or vasoactive intestinal peptide in the developing rat cerebral cortex.

Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow.

Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.

RATIONALE: Peroxisome proliferator-activated receptor (PPAR)γ agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPARγ, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs). OBJECTIVE: To determine whether a PPARγ agonist reduces angiotensin II (Ang II)-induced atherosclerosis and AAAs via interaction with SMC-specific PPARγ. METHODS AND RESULTS: Low-density lipoprotein receptor (LDLR)(-/-) mice with SMC-specific PPARγ deficiency were developed using PPARγ floxed (PPARγ(f/f)) and SM22 Cre(+) mice. PPARγ(f/f) littermates were generated that did not express Cre (Cre(0/0)) or were hemizygous for Cre (Cre(+/0)). To assess the contribution of SMC-specific PPARγ in ligand-mediated attenuation of Ang II-induced atherosclerosis and AAAs, both male and female Cre(0/0) and Cre(+/0) mice were fed a fat-enriched diet with or without the PPARγ agonist pioglitazone (Pio) (20 mg/kg per day) for 5 weeks. After 1 week of feeding modified diets, mice were infused with Ang II (1000 ng/kg per minute) for 4 weeks. SMC-specific PPARγ deficiency or Pio administration had no effect on plasma cholesterol concentrations. Pio administration attenuated Ang II-increased systolic blood pressure equivalently in both Cre(0/0) and Cre(+/0) groups. SMC-specific PPARγ deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre(0/0) mice, but not in mice with SMC-specific PPARγ deficiency. SMC-specific PPARγ deficiency or Pio administration had no effect on Ang II-induced AAA development. Pio also did not attenuate Ang II-induced monocyte chemoattractant protein-1 production in PPARγ-deficient SMCs. CONCLUSIONS: Pio attenuates Ang II-induced atherosclerosis via the interaction with SMC-specific PPARγ, but has no effect on the development of AAAs.