Regulation of coronary collateral growth by microrna-21 in metabolic syndrome
Well‐developed coronary collaterals prove to be highly beneficial in salvaging ischemic myocardium, preserving cardiac function, and improving patient outcome post‐occlusion. However, this process of coronary collateral growth (CCG) is impaired in patients with metabolic syndrome. A complete understanding of the underlying mechanism, cell types, and genes contributing towards this impairment have yet to be elucidated. Therefore, uncovering more about the process may lead to potential therapeutics to induce CCG in metabolic syndrome. MicroRNA‐21 (miR‐21) is abundantly expressed in vascular and immune cells with numerous implications in cardiovascular disease including atherosclerosis, heart failure, and myocardial infarction. Furthermore, miR‐21 has been shown to regulate processes such as apoptosis, immune cell polarization, and endothelial progenitor proliferation. Additionally, miR‐21 dysregulation has been rooted in the diabetic population where lies a systemic inflammatory state. In this study, we investigated the role of miR‐21 in a mouse model of CCG. Our preliminary data suggested that down‐regulating miR‐21 rescues impaired CCG in a diet‐induced model of metabolic syndrome. Thus, we investigated the underlying mechanism and focused on the roles of miR‐21 in the maintenance of vascular homeostasis, function and inflammatory responses in metabolic syndrome. First, we studied whether miR‐21 regulates endothelial homeostasis by modulating the function and homing of bone marrow stem cells in metabolic syndrome. We analyzed endothelial progenitor cells (CD34+) in bone marrow and peripheral blood, along with endothelial proliferation in WT, miR‐21 knockout, and metabolic syndrome mice. Second, we studied whether miR‐21 regulates the inflammatory response in metabolic syndrome by characterizing bone marrow derived macrophages from WT and miR‐21 knockout animals along with mapping their influence on vascular cells. Third, we utilized a myeloid specific miR‐21 knockout to study its role during CCG in vivo. We found CCG to be blunted in these animals which suggests the importance of myeloid derived miR‐21 in healthy mice. Further studies will give us more insight on miR‐21 and its regulation of CCG in metabolic syndrome.
Juguilon C;Richardson D;Gadd J;Enrick M;Jamaiyar A;Xu Y;Wang Z;Wang T;Kolz C;Chilian W;Yin L
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.09506" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.09506</a>
Sprouting angiogenesis contributes to coronary collateral growth induced by repetitive ischemia in adult mice
In the United States, coronary heart diseases (CHD) are the leading cause of mortality and morbidity. A well‐developed coronary collateral circulation ameliorates the consequences of CHD, reducing the incidence of sudden death and infarct sizes following coronary occlusion. Stimulation of coronary collateral growth (CCG) is also an alternative therapeutic approach to patients with intractable angina pectoris. The importance of CCG is undisputable, but the process and mechanism underlying CCG is unclear. We developed a mouse model of CCG induced by repetitive ischemia (RI) and validated CCG by contrast echocardiography to measure the coronary blood flow in the normal zone (NZ) and the collateral dependent zone (CZ). We also used Micro‐CT scans to reconstruct the coronary vasculature in 3D and quantify CCG. In this study, we crossed ROSA mT/mG double fluorescent reporter mice with cell type‐specific cre mice to investigate the roles that different cell‐types play at various stages of CCG. Mice were subjected to the RI protocol and their cardiac function and coronary blood flow was measured by echocardiography. Following sacrifice, hearts were fixed for immunostaining or imaging under confocal and multiphoton microscopy. In ROSA mT/mG floxed, Apln cre mouse hearts, large vessels (diameter of 20–50 μm) expressing GFP were identified in the collateral dependent zone in the early stage of RI, indicating that they originated from sprouting endothelial cells. At the end of RI, a complete network of these vessels was observed anastomosing with existing vasculature from the NZ. Immunostaining revealed an outer layer of smooth muscle cells in these vessels, suggesting the arteriogenesis or arterialization. Interestingly, in ROSA mT/mG floxed, Lyz2 cre mouse hearts, GFP expressing myeloid cells were observed in high numbers around newly formed large vessels, suggesting that immune cell recruitment occurs in the early stages of CCG. Our preliminary data show that coronary collaterals form in response to RI, are of microvascular origin and are associated with early recruitment of immune cells to the CZ. Our further study will focus on the process of CCG in greater detail at the molecular and cellular level, potentially leading toward a therapeutic application of induced CCG in patients of ischemic heart diseases.
Jamaiyar A;Juguilon C;Richardson D;Gadd J;Wang T;Enrick M;Goodner R;Chilian W;Yin L
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.09453" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.09453</a>
Is chemotherapy-induced cardiomyopathy caused by myocardial ischemia?
Over the last 50 years progress has been made in treating childhood and adult solid and hematological tumors. One commonly used chemotherapeutic agent is doxorubicin (DOX), an anthracycline antitumor antibiotic, which was discovered in early 1960s. Anthracycline (ANT) chemotherapy alone or in combination with other chemotherapeutic agents markedly improves the survival rate of cancer patients, particularly among children, where survival rates have more than doubled over 5 decades. However, the use of ANT chemotherapy is a double‐edged sword in that it can produce chemotherapy induced cardiac dysfunction (CRCD), which can cause death in 50% of the patients with who present with the cardiomyopathy. We hypothesized, that one of the causes for CRGD is a reduction in myocardial blood flow (MBF) that leads to cardiac myocyte hypoxia, producing small areas of ischemia and myocyte damage. We also hypothesize that increasing MBF by the coronary vasodilator chromonar prevents cardiomyocytes from hypoxic damage. To test these hypotheses, we treated mice genetically engineered to show cardiac myocyte fluorescence if the cells are hypoxic (hypoxia fate mapping [HFM]) with DOX for 6 weeks (group 1, N=8) and Dox + Chromonar for 6 weeks (group 2 N=8). Five weeks after treatment we started tamoxifen for 5 days to activate the HFM protocol. Tamoxifen induces Cre in cardiac myocytes and hypoxia activates a program that results in the expression of td‐tomato only in hypoxic cardiac myocytes. In tissue sections, hypoxic cardiac myocytes are visualized by fluorescence microscopy. Cardiac function was measured by ultrasound and MBF was measured with contrast echocardiography. Six weeks after DOX treatment many hypoxic myocytes were observed in the myocardium. Cardiac function was significantly decreased at the end of DOX treatment (% ejection fraction EF=39±3) compared to baseline (62±5.8%). Simultaneous administration of chromonar prevents the cardiomyocytes from hypoxic damage and prevents cardiac dysfunction development. %EF was 58±6 at the end of the chemotherapy. Chromonar also significantly increased MBF in group 2 mice compared to group 1 (P<0.05). Based on these data CRCD may be a type of ischemic heart disease where the treatment reduces MBF, which leads cardiomyocyte hypoxia, and causes progressive, accumulative cardiac injury. Moreover, increasing myocardial blood flow by chromonar prevents the cardiomyocytes from hypoxic damage and development of CRCD.
Davidian A;Mistry M;Pucci T;Kolz C;Shockling L;Enrick M;Yin L;Chilian W;Ohanyan V
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.05328" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.05328</a>
Is heart failure a coronary microvascular disorder?
HEART failure; MICROCIRCULATION disorders; COMPRESSIVE force; ENDOTHELIUM diseases
Ohanyan V; Hakobyan T; Shockling L; Gyulkhasyan T; Enrick M; Kolz C L; Chilian W M
Proceedings Of The Physiological Society
2019
2019-01
Journal Article
n/a
Stem Cell Therapies For Coronary Collateral Growth In Zucker Obese Fatty Rats: Redox Modulator Mitoneet As A Therapeutic Target
Arteriogenesis; Cardiovascular System & Cardiology; cells; Metabolic syndrome; Mitochondria; oxidative stress; Stem
Logan S; Geldenhuys W; Yin L Y; Carroll R; Stevanov K; Enrick M; Ohanyan V; Chilian W
Circulation
2013
2013-11
Journal Article or Conference Abstract Publication
n/a
Failure Of Regenerative Cell-based Therapy To Stimulate Coronary Collateral Growth In A Rat Model Of Metabolic Syndrome
Arteriogenesis; Cardiovascular System & Cardiology; Collateral circulation; Metabolic; oxidative stress; Stem cell therapy; syndrome
Logan S; Chilian W M; Ohanyan V A; Stevanov K; Enrick M; Kolz C L; Yin L Y
Circulation
2012
2012-11
Journal Article or Conference Abstract Publication
n/a
Trpv1 Channels In The Heart: A Novel Redox Sensor?
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Kmetz J G; Ohanyan V; Enrick M; Kang P T; Chen C L; Chen Y R; Bratz I N
Faseb Journal
2012
2012-04
Journal Article or Conference Abstract Publication
n/a
Lack Of Efficient Metabolism Adaption Caused Failure Of Regenerative Cell-based Therapy In A Rat Model Of Metabolic Syndrome
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Jamaiyar A; Wan W G; Janota D; Enrick M; Ohanyan V; Yin L; Chilian W
Faseb Journal
2017
2017-04
Journal Article or Conference Abstract Publication
n/a
The Role Of Leptin In Coronary Collateral Growth
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Graham K; Ohanyan V; Enrick M; Kolz C; Chilian W M; Yin L Y
Faseb Journal
2017
2017-04
Journal Article or Conference Abstract Publication
n/a
Inducible vascular progenitor cells grown on the biodegradable polymer bundles in the cardiovascular regeneration
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Yin L Y; Ohanyan V; Enrick M; Stevanov K; Song H Y; Kolz C; Logan S; Newby B M Z; Chilian W
Faseb Journal
2014
2014-04
Journal Article
n/a
Induced Vascular Progenitor Cells Derived From Endothelial Cells Stimulate Coronary Collateral Growth
Cardiovascular System & Cardiology; Collateral circulation
Yin L Y; Ohanyan V; Pung Y F; Delucia A L; Bailey E; Enrick M; Stevanov K; Kolz C L; Guarini G; Chilian W
Circulation
2011
2011-11
Journal Article
n/a
Is Heart Failure a Coronary Microvascular Disease?
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Rinker L; Yin L Y; Hakobyan T; Enrick M; Kolz C; Nadler N; Chao J; Sim D; Hopman P; Chilian W; Ohanyan V
Faseb Journal
2017
2017-04
Journal Article
n/a
Role of Kv 1.5 Channels in Regulation of Myocardial Oxygen Balance
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Ohanyan V; Yin L Y; Enrick M; Nagane M; Hou H G; Hakobyan T; Kolz C; Kuppusamy P; Chilian W
Faseb Journal
2015
2015-04
Journal Article
n/a
The Role of Vascular Smooth Muscle Kv 1.5 Channels in Coronary Metabolic Dilation
Blood; Cardiovascular System & Cardiology; Coronary circulation; flow; Heart failure; Ion channels; Smooth muscle
Ohanyan V A; Luli J; Yin L Y; Logan S; Enrick M; Stevanov K; Kolz C L; Kmetz J; Bratz I; Chilian W M
Circulation
2013
2013-11
Journal Article
n/a
Mouse Model of Takotsubo Cardiomyopathy: The Role of Coronary Metabolic Blood Flow Regulation in Apical Ballooning
blood-flow; Cardiovascular disease; Cardiovascular System & Cardiology; Heart disease; Myocardial perfusion; Stress echocardiography
Ohanyan V A; Luli J; Yin L Y; Enrick M; Stevanov K; Kolz C L; Logan S; Chilian W M
Circulation
2013
2013-11
Journal Article
n/a
Impaired Coronary Metabolic Dilation Leads to Heart Failure During Pressure Overload
Aortic stenosis; Cardiovascular System & Cardiology; Coronary circulation; Heart failure; Ion channels; Potassium channel
Ohanyan V A; Luther D; Kolz C; Logan S; Enrick M; Stevanov K; Yin L Y; Chilian W
Circulation
2012
2012-11
Journal Article
n/a
Impaired Coupling of Myocardial Blood Flow to Cardiac Work Leads to Cardiac Dysfunction
Cardiovascular; Cardiovascular System & Cardiology; Coronary vessels; Ion channels; Metabolic; Redox; syndrome
Ohanyan V A; Yin L Y; Pung Y F; Enrick M; Hakobyan T A; Kolz C L; Logan S; Bratz I; Chilian W M
Circulation
2011
2011-11
Journal Article
n/a
Gender differences in cardiac function of Kv1.5-/- mice during aging
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Ohanyan V; Yin L Y; Logan S; Enrick M; Hakobyan T; Kolz C L; Pung Y F; Bratz I; Chilian W
Faseb Journal
2012
2012-04
Journal Article
n/a
Catecholamine Induced Takotsubo Cardiomyopathy: The role of coronary metabolic blood flow regulation in apical ballooning
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Ohanyan V; Yin L; Bardakjian R; Khayata M; Kolz C L; Enrick M; Schatmeyer B; Perera V; Janota D; Hakobyan T; Chilian W M
Faseb Journal
2016
2016-04
Journal Article
n/a