Cardiac Rehabilitation After Heart Valve Surgery: COMPARISON WITH CORONARY ARTERY BYPASS GRAFT PATIENTS.

PURPOSE: Coronary artery bypass graft (CABG) surgery patients participating in cardiac rehabilitation (CR) experience improvements in aerobic fitness, but there has been little study of outcomes for heart valve (HV) surgical patients. The primary aims of this study were to evaluate baseline peak aerobic capacity for HV patients participating in CR and to compare outcomes between HV and CABG patients. METHODS: Five hundred seventy-six consecutive patients who underwent HV surgery (n = 125), HV plus CABG surgery (n = 57), or CABG surgery (n = 394), all with classic sternotomy and enrolled in CR, were prospectively studied. Changes in outcomes were assessed for individuals who completed CR (n = 313). RESULTS: HV patients were significantly older and had a greater percentage of females than the CABG-only group. Combining HV and HV + CABG groups, valvular disorders included 134 mitral, 39 aortic, and 8 combined abnormalities (mitral and aortic). For the entire cohort, the mean number of CR exercise sessions attended was 23.6 ± 11.7. Peak oxygen uptake ((Equation is included in full-text article.)) increased 19.5% from 17.4 ± 4.4 to 20.8 ± 5.5 mLO2·kg(-1)·min(-1) (P < .0001). Improvement in peak (Equation is included in full-text article.)with CR exercise training was similar between the 3 groups of patients. Within the group of patients who had HV surgery, percentage change in peak (Equation is included in full-text article.)was not significantly different between the 3 types of valvular abnormalities (ie, mitral [19.2%], aortic [24.4%], and mitral + aortic [21.9%]). CONCLUSIONS: HV surgery patients achieve similar improvement in aerobic fitness from participating in CR exercise training as individuals who had CABG. The observed improvements in aerobic fitness are similar, regardless of the type of valve abnormality or whether CABG was performed concurrently.

EGLN3 prolyl hydroxylase regulates skeletal muscle differentiation and myogenin protein stability.

EGLN3, a member of the EGLN family of prolyl hydroxylases, has been shown to catalyze hydroxylation of the alpha subunit of hypoxia-inducible factor-alpha, which targets hypoxia-inducible factor-alpha for ubiquitination by a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor. We now report that EGLN3 levels increase during C2C12 skeletal myoblast differentiation. EGLN3 small interference RNAs and EGLN3 antisense oligonucleotides blocked C2C12 differentiation and decreased levels of myogenin, a member of the MyoD family of myogenic regulatory factors, which plays a critical role in myogenic differentiation. We also report that EGLN3 interacts with and stabilizes myogenin protein, whereas VHL associates with and destabilizes myogenin via the ubiquitin-proteasome system. The effect of VHL on myogenin stability and ubiquitination can be reversed, at least in part, by overexpression of EGLN3, suggesting that its binding to myogenin may prevent VHL-mediated degradation. These data demonstrate a novel role for EGLN3 in regulating skeletal muscle differentiation and gene expression. In addition, this report provides evidence for a novel pathway that regulates myogenin expression and skeletal muscle differentiation.

Regulation of the SM-20 prolyl hydroxylase gene in smooth muscle cells.

SM-20 encodes an intracellular prolyl hydroxylase that acts on hypoxia inducible factor (HIF)-1alpha, targeting it for proteasomal degradation. By decreasing HIF-alpha, SM-20 is thought to modulate the expression of hypoxia-regulated genes. SM-20 expression in the arterial wall is restricted to smooth muscle cells, which play a critical role in atherosclerosis and arterial injury. To further elucidate the regulation of SM-20 in smooth muscle, we cloned and analyzed the rat SM-20 promoter. In transient transfections, the SM-20 promoter displayed approximately 6-fold greater activity in smooth muscle cells vs. fibroblasts. Deletion analysis and electrophoretic mobility shift assays demonstrated that SM-20 transcription was regulated by two Sp1/Sp3 sites. A shift in binding to the Sp1/Sp3 sites, a decrease in Sp1 and Sp3 protein levels, and the emergence of a lower molecular weight form of Sp1 were seen in serum-deprived or post-confluent SMC, suggesting that SM-20 is regulated during smooth muscle cell differentiation.

Mammalian EGLN genes have distinct patterns of mRNA expression and regulation.

The mammalian EGLN family contains three paralagous genes (EGLN1, EGLN2, and EGLN3) encoding prolyl hydroxylase isoforms that mediate the oxygen-dependent targeting of the transcription factor hypoxia inducible factor alpha to the proteosome. The rat orthologue of EGLN3 (SM-20) exhibits tissue-restricted expression, is induced by growth factors in cultured vascular smooth muscle, and is up-regulated during myogenesis. To determine if all three EGLN genes are coordinately regulated, we examined their mRNA expression in murine tissues and in cultured cells. We now report that the three murine EGLN mRNAs have unique but overlapping patterns of tissue expression. The most striking differences were in the heart, where EGLN3 had its highest levels of expression, and the testis, where EGLN2 was the only isoform expressed. In cultured vascular smooth muscle cells, serum treatment led to up-regulation of EGLN1 and EGLN3, but not EGLN2, and only EGLN3 was superinduced by cyclohexamide. In cultured C2C12 myocytes, EGLN3 was up-regulated during differentiation, whereas EGLN1 and EGLN2 were constitutively expressed. The abundance of EGLN3 mRNA in the heart, its induction by growth factors in vascular smooth muscle, and its regulation during C2C12 differentiation suggest a unique role for EGLN3 and might justify the development of isoformspecific inhibitors.