All ETDs from UAB

Advisory Committee Chair

Qinglin Yang

Advisory Committee Members

Shannon Bailey

John Chatham

Pi-Ling Chang

Maria Deluca

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

Limited regeneration capacity is the main cause of heart failure following myocardial infarction (MI) in adult mammals. Emerging evidence supports that adult cardiomyocyte proliferation and myocardial angiogenesis could be enhanced, especially under MI condition. Peroxisome proliferator-activated receptor δ (PPARδ) is a key transcriptional regulator of lipid metabolism, mitochondrial biogenesis, anti-inflammation, and antioxidant defense in the heart. PPARδ signaling is involved in cell proliferation in many cell types. However, whether PPARδ is also determined cardiomyocyte proliferation and angiogenesis in the heart is unknown. Based on a high-through-put screening hit on cultured cardiomyocytes conducted by our collaborator, I have focused on establishing the in vivo effects of PPARδ signaling on adult cardiomyocyte proliferation. I assessed a mouse strain in which the expression of constitutively active PPARδ could be induced in the adult heart after a short-term treatment with tamoxifen (TMVPD) and a heterozygous tamoxifen-inducible cardiomyocyte-restricted PPARδ knockout mouse strain (TMPD+/-). Tamoxifen-induced, cardiomyocyte-restricted Cre expression mice (TMCM) were used as control. Heart sections were immunohistochemically stained for cell proliferation markers, such as BrdU-, H3P-, and Aurora B, demonstrating evidence of cardiomyocyte proliferation. When subjected to MI induced by left anterior descending artery (LAD) ligation, TMVPD mouse hearts showed a substantially greater increase of BrdU-, H3P-, and Aurora B staining than TMCM hearts, concomitant with improving cardiac function and smaller infarct size. Administration of PPARδ-selective ligand GW0742 exerted similar protective effect after MI, whereas this effect was partially abolished in TMPD+/- mice. Using cultured cardiomyocytes, we uncovered that PPARδ acted through the phosphoinositide-dependent kinase-1 (PDK1)/p308Akt and phosphorylated glycogen synthase kinase 3 beta (pGSK3β)/β-catenin signaling pathways to achieve the cardiomyocyte-proliferative effects. Furthermore, we revealed that activation of PPARδ by GW0742 promoted angiogenesis in infarcted hearts. The pro-angiogenesis was achieved through the upregulation of hypoxia inducible factor 1(HIF-1α) and vascular endothelial growth factor (VEGF). We conclude that PPARδ signaling in adult cardiomyocytes plays an important role in facilitating adult cardiomyocyte proliferation and angiogenesis, hence contributing to the myocardial protective effects of PPARδ activation.

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