PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia

Diabetes and hypercholesterolemia are two of the major risk factors for developing cardiovascular disease, especially in combination with chronic myocardial ischemia it represents one of the most common causes of disability or death. New pro-angiogenic factors like Thymosin ß4 (Tß4), a small 4.9 kDa peptide influences cell motility and migration might be suitable for inducing therapeutic neovascularization in chronic myocardial ischemia a cardiovascular risk factors. Methods: Chronic ischemia was induced via reduction stent graft in the circumflex artery, leading to a total occlusion on day 28 (d28). Beside wildtyp animals (wt) ± high fat diet (hypercholesteric (hyp), choselsterol 78±1 wt vs 90±2 hyp), d iabetic transgenic pigs were used (increased blood glucose 305 ±12 mg/dL) . Regional application of rAAV Tß4 (5x10E12 viral particles, d28) was performed in wt, hyp and diabetic pigs respectively. Global myocardial function was obtained at day 28 and 56. Regional myocardial function and post mortem angiography were examined on day 56. Histological analysis of capillary density (capillaries/field (C/F)) was performed in the ischemic tissue. Results: rAAV.Tß4 transduction significantly enhanced capillaries (278±6 vs. 148±6 c/hpf) and collaterals (9±1 vs. 3±1) compared to control wt animals. Furthermore, global (EF: 47±4 vs. 29±3 %); and regional myocardial function (SES at 150 b/min: 73±5 vs. 10±6 % of non-ischemic area) were increased after Tß4 overexpression. In the models of cardiovascular risk factors and chronic myocardial ischemia increased neovascularization and improved myocardial function could be achieved after rAAV Tß4 application, albeit at a lower level (capillaries: diabetic: 190±4 (Tß4) vs. 120±5 (control) c/hpf hyp: 188±6 (Tß4) vs 130±12 (control) c/hpf; collaterals: diabetic: 4±1 (Tß4) vs. 2±1 (control) hyp: 6±1 (Tß4) vs 3±1 (control); EF: diabetic: 32±2 % (Tß4) vs. 27±1 % (control) hyp: 42±4 % (Tß4) vs 28±3 % (control)). Conclusion: Long term Thymosin ß4 expression induced neovascularization and improved myocardial perfusion and function even in pigs with additional risk factors. Therefore, rAAV.Tß4 appears suitable for treatment of ischemic cardiomyopathy associated with these cardiovascular risk factors.

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Clinical Gene and Stem Cell Therapy in Patients with Acute and Chronic Myocardial Ischemia

Adult and Pluripotent Stem Cells ◽

10.1007/978-94-017-8657-7_8 ◽

2014 ◽

pp. 143-167

Author(s):

Jens Kastrup ◽

Annette Ekblond ◽

Mandana Haack-Sørensen ◽

Anders B. Mathiasen ◽

Abbas A. Qayyum

Keyword(s):

Stem Cell ◽

Myocardial Ischemia ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Chronic Myocardial Ischemia

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Coronary Collateral Circulation in Acute and Chronic Myocardial Ischemia

Microcirculation in Circulatory Disorders ◽

10.1007/978-4-431-68078-9_42 ◽

1988 ◽

pp. 323-325

Author(s):

Bernd Winkler ◽

Thomas Schmidt ◽

Wolfgang Schaper

Keyword(s):

Myocardial Ischemia ◽

Collateral Circulation ◽

Coronary Collateral Circulation ◽

Coronary Collateral ◽

Chronic Myocardial Ischemia

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Resveratrol Improves Myocardial Perfusion in a Swine Model of Hypercholesterolemia and Chronic Myocardial Ischemia

Circulation ◽

10.1161/circulationaha.109.920132 ◽

2010 ◽

Vol 122 (11_suppl_1) ◽

pp. S142-S149 ◽

Cited By ~ 74

Author(s):

M. P. Robich ◽

R. M. Osipov ◽

R. Nezafat ◽

J. Feng ◽

R. T. Clements ◽

...

Keyword(s):

Myocardial Perfusion ◽

Myocardial Ischemia ◽

Swine Model ◽

Chronic Myocardial Ischemia

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Protamine inhibits coronary collateral development in a canine model of repetitive coronary occlusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.2.h720 ◽

1995 ◽

Vol 268 (2) ◽

pp. H720-H728 ◽

Cited By ~ 8

Author(s):

J. R. Kersten ◽

P. S. Pagel ◽

D. C. Warltier

Keyword(s):

Blood Flow ◽

Myocardial Ischemia ◽

Contractile Function ◽

Regional Myocardial Blood Flow ◽

Collateral Development ◽

Coronary Collateral ◽

Debt Repayment ◽

Chronic Myocardial Ischemia

Protamine has been demonstrated to inhibit angiogenesis in vitro and in vivo; however, its effect on coronary collateral development has not been examined. The present investigation tested the hypothesis that subcutaneously administered protamine inhibits canine coronary collateral development in response to chronic myocardial ischemia. Dogs underwent daily, repetitive, 2-min, left anterior descending coronary artery (LAD) occlusions for 22 consecutive days. Regional myocardial blood flow (radioactive microspheres), LAD segment shortening, and coronary flow debt repayment were measured in saline-treated (n = 7) and protamine-treated (n = 6) dogs on days 1, 8, 15, and 22. Coronary collateral development in saline-treated dogs was demonstrated by time-dependent significant (P < 0.05) increases in collateral blood flow to ischemic myocardium [day 1 0.10 +/- 0.01 vs. day 22 0.88 +/- 0.05 (SE) ml.min-1.g-1], progressive normalization of myocardial contractile function during LAD occlusion, and successive reduction in flow debt repayment. In contrast, protamine treatment significantly attenuated, increases in collateral perfusion (day 1 0.13 +/- 0.02 vs. day 22 0.36 +/- 0.03 ml.min-1.g-1). Regional contractile dysfunction and postocclusive reactive hyperemic responses were sustained over time in protamine-treated compared with saline-treated dogs. The results demonstrate that protamine inhibits coronary collateral development in response to chronic myocardial ischemia.

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Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.3.h930 ◽

1998 ◽

Vol 274 (3) ◽

pp. H930-H936 ◽

Cited By ~ 4

Author(s):

John J. Lopez ◽

Elazer R. Edelman ◽

Alon Stamler ◽

Mark G. Hibberd ◽

Pottumarthi Prasad ◽

...

Keyword(s):

Growth Factors ◽

Myocardial Ischemia ◽

Left Ventricular Function ◽

Ventricular Function ◽

Coronary Flow ◽

Genetically Modified ◽

Left Ventricular ◽

Heparin Binding ◽

Regional Left Ventricular Function ◽

Chronic Myocardial Ischemia

A number of heparin-binding growth factors, including basic (bFGF) and acidic (aFGF) fibroblast growth factors have been shown to promote angiogenesis in vivo. In this study, we employed a sustained-release polymer extravascular delivery system to evaluate the angiogenic efficacy of a novel form of genetically modified aFGF in the setting of chronic myocardial ischemia. Fifteen Yorkshire pigs subjected to Ameroid occluder placement on the left circumflex (LCX) artery were treated with perivascularly administered aFGF in ethylene vinyl acetate (EVAc) polymer (10 μg, n = 7) or EVAc alone (controls, n = 8). Seven to nine weeks later, after coronary angiography to document Ameroid-induced coronary occlusion, all animals underwent studies of coronary flow and global and regional left ventricular function. Microsphere-determined coronary flow in the Ameroid-compromised territory was significantly increased in aFGF-treated compared with control animals, and this improvement in perfusion was maintained during ventricular pacing. Left ventricular function studies demonstrated improved global and regional function in aFGF-treated animals. We conclude that local perivascular delivery of genetically modified aFGF results in significant improvement in myocardial flow and regional and global left ventricular function.

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