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Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.

ABSTRACT: We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.

SUBMITTER: Cowan DB

PROVIDER: S-EPMC4976938 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.

Cowan Douglas B DB Yao Rouan R Akurathi Vamsidhar V Snay Erin R ER Thedsanamoorthy Jerusha K JK Zurakowski David D Ericsson Maria M Friehs Ingeborg I Wu Yaotang Y Levitsky Sidney S Del Nido Pedro J PJ Packard Alan B AB McCully James D JD

PloS one 20160808 8

We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the hea ...[more]

PMID: 27500955

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Project description:BackgroundWomen who deliver pre-term have been reported to have increased future risks of cardiometabolic disorders. However, their long-term risks of ischemic heart disease (IHD) and whether such risks are due to shared familial factors are unclear. A better understanding of these risks may help improve long-term clinical follow-up and interventions to prevent IHD in women.ObjectivesThe purpose of this study was to determine the long-term risks of IHD in women by pregnancy duration.MethodsA national cohort study was conducted of all 2,189,190 women with a singleton delivery in Sweden from 1973 to 2015, who were followed up for IHD through the end of 2015. Cox regression was used to compute adjusted hazard ratios (aHRs) for IHD associated with pregnancy duration, and cosibling analyses assessed the influence of shared familial (genetic and/or environmental) factors.ResultsIn 47.5 million person-years of follow-up, 49,955 (2.3%) women were diagnosed with IHD. In the 10 years following delivery, the aHR for IHD associated with pre-term delivery (<37 weeks) was 2.47 (95% confidence interval [CI]: 2.16 to 2.82), and further stratified was 4.04 (95% CI: 2.69 to 6.08) for extremely pre-term (22 to 27 weeks), 2.62 (95% CI: 2.09 to 3.29) for very pre-term (28 to 33 weeks), 2.30 (95% CI: 1.97 to 2.70) for late pre-term (34 to 36 weeks), and 1.47 (95% CI: 1.30 to 1.65) for early-term (37 to 38 weeks), compared with full-term (39 to 41 weeks). These risks declined but remained significantly elevated after additional follow-up (pre-term vs. full-term, 10 to 19 years: aHR: 1.86; 95% CI: 1.73 to 1.99; 20 to 29 years: aHR: 1.52; 95% CI: 1.45 to 1.59; 30 to 43 years: aHR: 1.38; 95% CI: 1.32 to 1.45). These findings did not appear attributable to shared genetic or environmental factors within families. Additional pre-term deliveries were associated with further increases in risk.ConclusionsIn this large national cohort, pre-term delivery was a strong independent risk factor for IHD. This association waned over time but remained substantially elevated up to 40 years later. Pre-term delivery should be recognized as a risk factor for IHD in women across the life course.

Dataset Information

Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.

Publications

Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.

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