Therapeutic Implications of PPARγ in Cardiovascular Diseases

Peroxisome proliferator-activated receptor-γ (PPARγ) is the members of the nuclear receptor superfamily as a master transcriptional factor that promotes differentiation of preadipocytes by activating adipose-specific gene expression. Although PPARγ is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, PPARγ is also present in a variety of cell types including vascular cells and cardiomyocytes. Activation of PPARγ suppresses production of inflammatory cytokines, and there is accumulating data that PPARγ ligands exert antihypertrophy of cardiomyocytes and anti-inflammatory, antioxidative, and antiproliferative effects on vascular wall cells and cardiomyocytes. In addition, activation of PPARγ is implicated in the regulation of endothelial function, proliferation and migration of vascular smooth muscle cells, and activation of macrophages. Many studies suggest that PPARγ ligands not only ameliorate insulin sensitivity, but also have pleiotropic effects on the pathophysiology of atherosclerosis, cardiac hypertrophy, ischemic heart, and myocarditis

Low atrial septal pacing with dual-chamber pacemakers reduces atrial fibrillation in sick sinus syndrome

SummaryBackgroundSick sinus syndrome (SSS) is often complicated with the additional presence of atrial fibrillation (AF). Atrial septal pacing, compared with right atrial appendage (RAA) pacing, shortens the atrial conduction time and reduces the dispersion of the refractoriness. However, low atrial septal (LAS) pacing's efficacy for preventing AF in SSS remains controversial in Japan.Methods and resultsWe analyzed 95 consecutive patients with SSS who underwent dual-chamber pacemaker implantations. Forty-two patients (44%) had a history of AF at the time of the pacemaker implantation. In the group without a history of AF, LAS pacing was performed in 17 patients, and RAA pacing in 36 patients. In the group with a history of AF, LAS pacing was performed in 15 patients, and RAA pacing in 27 patients. We evaluated whether LAS pacing prevented the development of de novo AF and the persistence of AF after pacemaker implantations. No significant differences were found in the baseline characteristics between the RAA and LAS groups regardless of an AF history. During a 1-year follow-up period, in the SSS patients without a history of AF, 19.0% (7/36) of the RAA group developed de novo AF, however, 5.9% (1/17) of the LAS group developed de novo AF (p=0.20). On the other hand, in the SSS patients with a history of AF, 22.0% (6/27) of the RAA group developed persistent AF, but none of the LAS group developed any persistent AF (p=0.049). There were no post-operative complications related to the LAS pacing.ConclusionsLAS pacing is safe and feasible. LAS pacing may prevent the progression to persistent AF in SSS patients with dual-chamber pacemakers

Effect of vasodilators in patient with pulmonary hypertension associated with hemolytic anemia

AbstractPulmonary arterial hypertension (PAH) has been described to associate with hemolytic anemia in updated clinical classification of pulmonary hypertension. A 56-year-old woman, diagnosed with warm antibody autoimmune hemolytic anemia (AIHA), was treated with oral corticosteroids at the Department of Hematology, Osaka University Hospital for 30 years. Her AIHA worsened 3 months before the admission, and she was treated with rituximab and cyclosporine in combination with prednisolone. Soon after she left the hospital, she developed dyspnea on effort and leg edema, therefore she was re-admitted to the Department of Cardiovascular Medicine. Echocardiogram and cardiac catheterization demonstrated PAH associated with AIHA. She was treated with three types of vasodilatory agents, resulting in an improvement in pulmonary arterial pressure and pulmonary vascular resistance after 6 weeks. A few weeks after she left the hospital, her hemolytic anemia became in remission without intensifying AIHA therapy, and did not worsen for a year of follow-up. Although corticosteroids are the first-line treatment for AIHA, medications for PAH should be considered when the first-line therapy for AIHA failed to improve PAH

A novel LIM protein Cal promotes cardiac differentiation by association with CSX/NKX2-5

The cardiac homeobox transcription factor CSX/NKX2-5 plays an important role in vertebrate heart development. Using a yeast two-hybrid screening, we identified a novel LIM domain–containing protein, named CSX-associated LIM protein (Cal), that interacts with CSX/NKX2-5. CSX/NKX2-5 and Cal associate with each other both in vivo and in vitro, and the LIM domains of Cal and the homeodomain of CSX/NKX2-5 were necessary for mutual binding. Cal itself possessed the transcription-promoting activity, and cotransfection of Cal enhanced CSX/NKX2-5–induced activation of atrial natriuretic peptide gene promoter. Cal contained a functional nuclear export signal and shuttled from the cytoplasm into the nucleus in response to calcium. Accumulation of Cal in the nucleus of P19CL6 cells promoted myocardial cell differentiation accompanied by increased expression levels of the target genes of CSX/NKX2-5. These results suggest that a novel LIM protein Cal induces cardiomyocyte differentiation through its dynamic intracellular shuttling and association with CSX/NKX2-5

Heat shock transcription factor 1 preserves cardiac angiogenesis and adaptation during pressure overload

To examine how heat shock transcription factor 1 (HSF1) protects against maladaptive hypertrophy during pressure overload, we subjected HSF1 transgenic (TG), knockout (KO) and wild type (WT) mice to a constriction of transverse aorta (TAC), and found that cardiac hypertrophy, functions and angiogenesis were well preserved in TG mice but were decreased in KO mice compared to WT ones at 4 weeks, which was related to HIF-1 and p53 expression. Inhibition of angiogenesis suppressed cardiac adaptation in TG mice while overexpression of angiogenesis factors improved maladaptive hypertrophy in KO mice. In vitro formation of vasculatures by microvascular endothelial cells was higher in TG mice but lower in KO mice than in WT ones. A siRNA of p53 but not a HIF-1 gene significantly reversed maladaptive hypertrophy in KO mice whereas a siRNA of HIF-1 but not a p53 gene induced maladaptive hypertrophy in TG mice. Heart microRNA analysis showed that miR-378 and miR-379 were differently changed among the three mice after TAC, and miR-378 or siRNA of miR-379 could maintain cardiac adaptation in WT mice. These results indicate that HSF1 preserves cardiac adaptation during pressure overload through p53-HIF-1-associated angiogenesis, which is controlled by miR-378 and miR-379

Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle

The concept of the plasticity or transdifferentiation of adult stem cells has been challenged by the phenomenon of cell fusion. In this work, we examined whether neonatal cardiomyocytes fuse with various somatic cells including endothelial cells, cardiac fibroblasts, bone marrow cells, and endothelial progenitor cells spontaneously in vitro. When cardiomyocytes were cocultured with endothelial cells or cardiac fibroblasts, they fused and showed phenotypes of cardiomyocytes. Furthermore, cardiomyocytes reentered the G2-M phase in the cell cycle after fusing with proliferative noncardiomyocytes. Transplanted endothelial cells or skeletal muscle–derived cells fused with adult cardiomyocytes in vivo. In the cryoinjured heart, there were Ki67-positive cells that expressed both cardiac and endothelial lineage marker proteins. These results suggest that cardiomyocytes fuse with other cells and enter the cell cycle by maintaining their phenotypes