Myeloid Derived miR‐21 Influences Coronary Collateral Growth in Metabolic Syndrome

Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague-Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome- c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (∼50%). Neutrophils increased transiently on day 3 RI in the collateral-dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (∼75%) while increasing Bax/Bax dimers, cytochrome- c release, and caspase activation (∼70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (∼60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21-dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation.

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miR‐mediated regulation of coronary collateral growth in the metabolic syndrome

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.1055.4 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

REBECCCA LYNN HUTCHESON ◽

ERIKA SMITH ◽

ALLA MUSIYENKO ◽

PETRA ROCIC

Keyword(s):

Metabolic Syndrome ◽

Coronary Collateral ◽

The Metabolic Syndrome ◽

Collateral Growth ◽

Coronary Collateral Growth

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Why is coronary collateral growth impaired in type II diabetes and the metabolic syndrome?

Vascular Pharmacology ◽

10.1016/j.vph.2012.02.001 ◽

2012 ◽

Vol 57 (5-6) ◽

pp. 179-186 ◽

Cited By ~ 24

Author(s):

Petra Rocic

Keyword(s):

Metabolic Syndrome ◽

Type Ii Diabetes ◽

Type Ii ◽

Coronary Collateral ◽

The Metabolic Syndrome ◽

Collateral Growth ◽

Coronary Collateral Growth

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Abstract P168: 20-HETE-mediated Neutrophil Adhesion Impairs Coronary Collateral Growth in Metabolic Syndrome

Hypertension ◽

10.1161/hyp.68.suppl_1.p168 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Gregory Joseph ◽

Amanda Soler ◽

Rebecca Hutcheson ◽

Ian Hunter ◽

Brenda Hutcheson ◽

...

Keyword(s):

Metabolic Syndrome ◽

Neutrophil Adhesion ◽

No Production ◽

Neutrophil Accumulation ◽

Coronary Collateral ◽

Sd Rats ◽

Collateral Growth ◽

Coronary Collateral Growth ◽

And Function ◽

Blocking Antibodies

Transient, repetitive myocardial ischemia (RI)-induced coronary collateral growth (CCG) is impaired in metabolic syndrome patients and animal models. Endothelial cell (EC) dysfunction and chronic inflammation are hallmarks of metabolic syndrome. We showed that while in normal animals (SD), RI induces transient infiltration of monocytes, associated with successful CCG, in metabolic syndrome rats (JCR), RI induces sustained accumulation of neutrophils, which contributes to compromised CCG. 20-hydroxyeicosatetraeonic acid (20-HETE) is a pro-inflammatory metabolite of arachidonic acid. Its role in the regulation of CCG is unknown. We hypothesized that enhanced 20-HETE-mediated neutrophil adhesion to ECs and consequent EC dysfunction and apoptosis result in impaired CCG in metabolic syndrome. P-selectin and ICAM-1 expression was increased ~40% in JCR vs. SD rats. This increase was prevented by 20-HETE antagonists, 20-SOLA or 20-HEDGE. 20-HETE antagonists also prevented neutrophil accumulation observed in JCR rats. Coronary arteries from JCR rats exhibited reduced endothelium (Ach)-dependent vasodilation (20% JCR vs. 50% of max. SD). RI-induced eNOS activation and NO production were likewise decreased (~60% and~70%, respectively) in JCR vs. SD rats. EC apoptosis (TUNEL) was severely increased in response to RI in JCR rats (~75% vs. SD). Neutrophil adhesion-blocking antibodies partially attenuated EC apoptosis (~70%) and EC dysfunction (~75% eNOS activation and NO production, 75% Ach-dependent vasodilation). 20-HETE antagonists fully reversed impaired endothelium-dependent vasodilation, eNOS activation, NO production and prevented EC apoptosis. Finally, impaired CCG in JCR rats (collateral-dependent blood flow, microspheres) was completely restored by 20-HETE antagonists (CZ/NZ flow was 0.76±0.07 in JCR+20-SOLA, 0.84±0.05 in JCR+20-HEDGE vs. 0.11±0.02 in JCR vs. 0.84±0.03 ml/min/g in SD rats) and partially restored by neutrophil-blocking antibodies (0.49±0.05 ml/min/g). Taken together, these results indicate that 20-HETE-dependent neutrophil adhesion and accumulation compromises EC survival and function leading to impaired CCG. 20-HETE antagonists could provide therapy for restoration of CCG in metabolic syndrome.

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Redox-sensitive Akt and Src regulate coronary collateral growth in metabolic syndrome

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00920.2008 ◽

2009 ◽

Vol 296 (6) ◽

pp. H1811-H1821 ◽

Cited By ~ 19

Author(s):

Ryan Reed ◽

Barry Potter ◽

Erika Smith ◽

Rashmi Jadhav ◽

Patricia Villalta ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Akt Activation ◽

Wky Rats ◽

Coronary Collateral ◽

Upstream Regulator ◽

Myocardial Oxidative Stress ◽

Collateral Growth ◽

Src Activation ◽

Coronary Collateral Growth

We have recently shown that the inability of repetitive ischemia (RI) to activate p38 MAPK (p38) and Akt in metabolic syndrome [JCR:LA-cp (JCR)] rats was associated with impaired coronary collateral growth (CCG). Furthermore, Akt and p38 activation correlated with optimal O2−· levels and were altered in JCR rats, and redox-sensitive p38 activation was required for CCG. Here, we determined whether the activation of Src, a possible upstream regulator, was altered in JCR rats and whether redox-dependent Src and Akt activation were required for CCG. CCG was assessed by myocardial blood flow (microspheres) and kinase activation was assessed by Western blot analysis in the normal zone and collateral-dependent zone (CZ). RI induced Src activation (∼3-fold) in healthy [Wistar-Kyoto (WKY)] animals but not in JCR animals. Akt inhibition decreased (∼50%), and Src inhibition blocked RI-induced CCG in WKY rats. Src inhibition decreased p38 and Akt activation. Myocardial oxidative stress (O2−· and oxidized/reduced thiols) was measured quantitatively (X-band electron paramagnetic resonance). An antioxidant, apocynin, reduced RI-induced oxidative stress in JCR rats to levels induced by RI in WKY rats versus the reduction in WKY rats to very low levels. This resulted in a significant restoration of p38 (∼80%), Akt (∼65%), and Src (∼90%) activation in JCR rats but decreased the activation in WKY rats (p38: ∼45%, Akt: ∼65%, and Src: ∼100%), correlating with reduced CZ flow in WKY rats (∼70%), but significantly restored CZ flow in JCR rats (∼75%). We conclude that 1) Akt and Src are required for CCG, 2) Src is a redox-sensitive upstream regulator of RI-induced p38 and Akt activation, and 3) optimal oxidative stress levels are required for RI-induced p38, Akt, and Src activation and CCG.

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Impaired Coronary Collateral Growth in the Metabolic Syndrome Is in Part Mediated by Matrix Metalloproteinase 12–Dependent Production of Endostatin and Angiostatin

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.113.301533 ◽

2013 ◽

Vol 33 (6) ◽

pp. 1339-1349 ◽

Cited By ~ 13

Author(s):

Tracy Dodd ◽

Luke Wiggins ◽

Rebecca Hutcheson ◽

Erika Smith ◽

Alla Musiyenko ◽

...

Keyword(s):

Metabolic Syndrome ◽

Matrix Metalloproteinase ◽

Coronary Collateral ◽

The Metabolic Syndrome ◽

Collateral Growth ◽

Coronary Collateral Growth ◽

Matrix Metalloproteinase 12

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miR‐21 normalizes vascular smooth muscle proliferation and improves coronary collateral growth in metabolic syndrome

The FASEB Journal ◽

10.1096/fj.14-251223 ◽

2014 ◽

Vol 28 (9) ◽

pp. 4088-4099 ◽

Cited By ~ 15

Author(s):

Rebecca Hutcheson ◽

Jennifer Chaplin ◽

Brenda Hutcheson ◽

Faye Borthwick ◽

Spencer Proctor ◽

...

Keyword(s):

Metabolic Syndrome ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Coronary Collateral ◽

Smooth Muscle Proliferation ◽

Collateral Growth ◽

Coronary Collateral Growth

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Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00561.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. H528-H540 ◽

Cited By ~ 16

Author(s):

Gregory Joseph ◽

Amanda Soler ◽

Rebecca Hutcheson ◽

Ian Hunter ◽

Chastity Bradford ◽

...

Keyword(s):

Metabolic Syndrome ◽

Endothelial Cell ◽

Endothelial Dysfunction ◽

Cell Survival ◽

Neutrophil Infiltration ◽

Coronary Collateral ◽

Endothelial Cell Survival ◽

Collateral Growth ◽

Neutrophil Depletion ◽

Coronary Collateral Growth

Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of MetS (JCR) completely restored and neutrophil depletion significantly improved CCG. We determined whether low endogenous levels of miR-145 in MetS allowed for elevated production of 20-hydroxyeicosatetraenoic acid (20-HETE), which, in turn, resulted in excessive neutrophil accumulation and endothelial dysfunction leading to impaired CCG. Rats underwent 0–9 days of repetitive ischemia (RI). RI-induced cardiac CYP4F (neutrophil-specific 20-HETE synthase) expression and 20-HETE levels were increased (4-fold) in JCR vs. normal rats. miR-145-Adv and 20-HETE antagonists abolished and neutrophil depletion (blocking antibodies) reduced (~60%) RI-induced increases in CYP4F expression and 20-HETE production in JCR rats. Impaired CCG in JCR rats (collateral-dependent blood flow using microspheres) was completely restored by 20-HETE antagonists [collateral-dependent zone (CZ)/normal zone (NZ) flow ratio was 0.76 ± 0.07 in JCR + 20-SOLA, 0.84 ± 0.05 in JCR + 20-HEDGE vs. 0.11 ± 0.02 in JCR vs. 0.84 ± 0.03 in normal rats]. In JCR rats, elevated 20-HETE was associated with excessive expression of endothelial adhesion molecules and neutrophil infiltration, which were reversed by miR-145-Adv. Endothelium-dependent vasodilation of coronary arteries, endothelial nitric oxide synthase (eNOS) Ser1179 phosphorylation, eNOS-dependent NO·− production and endothelial cell survival were compromised in JCR rats. These parameters of endothelial dysfunction were completely reversed by 20-HETE antagonism or miR-145-Adv delivery, whereas neutrophil depletion resulted in partial reversal (~70%). We conclude that low miR-145 in MetS allows for increased 20-HETE, mainly from neutrophils, which compromises endothelial cell survival and function leading to impaired CCG. 20-HETE antagonists could provide viable therapy for restoration of CCG in MetS. NEW & NOTEWORTHY Elevated 20-hydroxyeicosatetraenoic acid (20-HETE) impairs coronary collateral growth (CCG) in metabolic syndrome by eliciting endothelial dysfunction and apoptosis via excessive neutrophil infiltration. 20-HETE antagonists completely restore coronary collateral growth in metabolic syndrome. microRNA-145 (miR-145) is an upstream regulator of 20-HETE production in metabolic syndrome; low expression of miR-145 in metabolic syndrome promotes elevated production of 20-HETE.

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