The goal of this proposal is to study regulation of coronary microvascular resistance using concordant methodologies to approach the experiments from a variety of perspectives: from the study of signaling pathways activated by shear stress in arterioles, to the production of vasoactive factors by cardiac myocytes, and finally to quantifying non-linear dynamics of coronary vasomotion.
Our aims are to test the following hypotheses: 1. Production of vasoconstrictor substances during activation of alpha1-adrenergic receptors on cardiac myocytes is modulated by PO2 and oxygen consumpton of the myocytes. 2. Vasodilators produced by isolated myocytes during increases in oxygen consumption are different than those produced during hypoxia. The hypotheses in Aims 1 and 2 will be tested by assessing vasoactive effects of factors produced by freshly isolated cardiac myocytes under varying conditions, e.g., alterations in oxygen consumption, hypoxia. In an isolated arteriole preparation , administration of pharmacological antagonists, to block production of factors by cardiac myocytes or receptors on arterioles, will allow vasoactive products produced by the cardiac myocytes. This preparation allows direct evaluation of myocyte-derived factors without complicating vasoactive influences of shear stress or myogenic regulation. 3. Vasomotion in the coronary microcirculation during metabolic dilation or autoregulation is controlled by redundant endothelium- and cardiac myocyte-derived factors. The hypothesis in Aim 3 will be tested using an in vivo beating heart preparation enabling measurement of coronary microvascular vasomotion--dynamic fluctuations in tone of the resistance vessels--which titrates blood flow to metabolic demand in microvascular perfusion territories. We will quantify attributes of vasomotion using non-linear, mathematical analyses to derive correlation dimensions, power spectra, and Lyapunov exponents, and dissect the role of putative metabolites using inhibitors of their production, or antagonists to their receptors. We believe these analyses avoid some constraints associated with steady-state measurements of coronary microvascular parameters and engender new insight and sensitive quantification of factors that control coronary blood flow. 4. The mechanism of shear stress-dependent nitric oxide-mediated vasodilation in coronary arterioles involves cascade involving activation of src, phosphatidylinositol 3-kinase (PI3K), and the mitogen activated protein kinase p38. This hypothesis will be tested in isolated arterioles using antagonists to target the specific components of the signaling pathway. Solutions to the above hypotheses should contribute much to our understanding of the regulation of coronary blood flow. The multifaceted approaches will enable us to precisely, and unequivocally, test each of the above hypotheses.
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| Guarini, Giacinta; Kiyooka, Takahiko; Ohanyan, Vahagn et al. (2016) Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage. Basic Res Cardiol 111:29 |
| Pung, Yuh Fen; Sam, Wai Johnn; Stevanov, Kelly et al. (2013) Mitochondrial oxidative stress corrupts coronary collateral growth by activating adenosine monophosphate activated kinase-? signaling. Arterioscler Thromb Vasc Biol 33:1911-9 |
| Hardwick, James P; Eckman, Katie; Lee, Yoon Kwang et al. (2013) Eicosanoids in metabolic syndrome. Adv Pharmacol 66:157-266 |
| Pung, Yuh Fen; Sam, Wai Johnn; Hardwick, James P et al. (2013) The role of mitochondrial bioenergetics and reactive oxygen species in coronary collateral growth. Am J Physiol Heart Circ Physiol 305:H1275-80 |
| Chilian, William M; Penn, Marc S; Pung, Yuh Fen et al. (2012) Coronary collateral growth--back to the future. J Mol Cell Cardiol 52:905-11 |
| Yin, Liya; Ohanyan, Vahagn; Pung, Yuh Fen et al. (2012) Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth. Circ Res 110:241-52 |
| Pung, Yuh Fen; Rocic, Petra; Murphy, Michael P et al. (2012) Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats. Arterioscler Thromb Vasc Biol 32:325-34 |
| Belmadani, Souad; Matrougui, Khalid; Kolz, Chris et al. (2009) Amplification of coronary arteriogenic capacity of multipotent stromal cells by epidermal growth factor. Arterioscler Thromb Vasc Biol 29:802-8 |
| Yun, June; Rocic, Petra; Pung, Yuh Fen et al. (2009) Redox-dependent mechanisms in coronary collateral growth: the ""redox window"" hypothesis. Antioxid Redox Signal 11:1961-74 |
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