Abstract:Adenosine and high-concentration isoflurane are commonly used to induce hyperemia for assessment of coronary flow reserve (CFR) in mice, but high-concentration isoflurane may exacerbate cardiac dysfunction, leading to impaired CFR. However, there is no study be found comparing the effects of adenosine and isoflurane on CFR and corresponding cardiac function. High-resolution echocardiography and invasive hemodynamic assessment were performed in 20 mice 2 wk after transverse aortic constriction (TAC), aortic reg… Show more
“…The coronary flow reserve (CFR) was calculated as the ratio of peak blood flow velocity during hyperemia to peak blood flow velocity at baseline [20,21]. To determine the cardiac hypertrophy, heart weight (HW), heart/body weight (HW/WB) ratio and heart weight/tibia length ratio were measured at the end of experiments.…”
Rationale
Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development.
Objective
This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI.
Approach and results
Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2+/Sca1+ and NG2+/c-kit+ progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2 weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b+ macrophage infiltration into ischemic areas compared to that of WT mice.
Conclusion
Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the preexisting coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation.
“…The coronary flow reserve (CFR) was calculated as the ratio of peak blood flow velocity during hyperemia to peak blood flow velocity at baseline [20,21]. To determine the cardiac hypertrophy, heart weight (HW), heart/body weight (HW/WB) ratio and heart weight/tibia length ratio were measured at the end of experiments.…”
Rationale
Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development.
Objective
This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI.
Approach and results
Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2+/Sca1+ and NG2+/c-kit+ progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2 weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b+ macrophage infiltration into ischemic areas compared to that of WT mice.
Conclusion
Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the preexisting coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation.
“…The coronary flow reserve (CFR) is expressed as the ratio of peak blood flow velocity during hyperemia to peak blood flow velocity at baseline [22;23]. …”
Rationale
Sirtuin (SIRT3), a major nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase in mitochondria, declines with aging and its ablation is associated with accelerated development of cardiovascular diseases. However, the role of SIRT3 in coronary microvascular function and post-MI recovery has not been incompletely understood.
Objective
The goal was to investigate whether ablation of SIRT3 causes coronary microvascular dysfunction, exacerbates post-myocardial ischemia (MI) cardiac dysfunction and impairs cardiac recovery.
Methods and results
Using endothelial cells (ECs) isolated from SIRT3 knockout (KO) mice, we revealed that the angiogenic capabilities were significantly reduced in SIRT3 deficient ECs. SIRT3 KO mice presented a pre-existing coronary microvascular dysfunction and microvascular rarefaction, as evidenced by a reduction in hyperemic peak diastolic blood flow velocity and coronary flow reserve (CFR), accompanied by loss of capillary-pericytes in the heart. Furthermore, SIRT3 KO mice subjected to myocardial ischemia by the ligation of left anterior descending coronary artery (LAD) exhibited more severe cardiac dysfunction together with decreased pericyte/EC coverage than that of WT mice. In contrast, overexpression of SIRT3 preserved cardiac function in post-MI mice. Immunoblot analysis further showed that the expression of angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were significantly decreased in the SIRT3-deficient ischemic hearts than those of WT ischemic hearts. This was accompanied by higher levels of cleaved caspase-3 and apoptosis.
Conclusion
Our results reveal a potential mechanism by which SIRT3 deletion exacerbates post-MI cardiac dysfunction and impairment of cardiac recovery involving microvascular rarefaction and pre-existing coronary microvascular dysfunction.
“…Severe aortic regurgitation was induced in the animals by retrograde puncture of the aortic valve leaflets, as described previously 10 , 13 . Briefly, the mice were anesthetized by intraperitoneal injection of a mixture of ketamine (150 mg/kg) and xylazine (10 mg/kg).…”
Section: Methodsmentioning
confidence: 99%
“…At 4 weeks after surgery, aortic regurgitation was considered severe if echocardiography showed remarkably increased LV dilatation (end‐diastolic dimension >4.5 mm) and the presence of retrograde holo‐diastolic flow in the proximal descending aorta with an end‐diastolic velocity higher than 300 mm/s. According to our and others' previous studies, an end‐diastolic velocity higher than 300 mm/s caused conspicuous eccentric LV hypertrophy 10 , 13 . Animals that did not fulfill these echocardiographic criteria were not included in the study.…”
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