Thioredoxin-1 Gene Therapy Enhances Angiogenic Signaling and Reduces Ventricular Remodeling in Infarcted Myocardium of Diabetic Rats

Q: What are the key findings of this study?

Intramyocardial Ad.Trx1 gene therapy significantly improved left ventricular ejection fraction (45.3% vs 38.5%) and capillary density (2450 vs 1773 counts/mm2) at 30 days in diabetic infarcted rats.

Q: What is the clinical evidence from this study?

Population: Myocardial infarction in streptozotocin-induced type 1 diabetic rats. Intervention: Adenoviral vector encoding thioredoxin-1 (Ad.Trx1) gene therapy vs. Ad.LacZ (1 x 10^9 pfu) and untreated diabetic myocardial infarction controls. Primary outcome: Left ventricular ejection fraction at 30 days (p=<=0.05).

Q: What does this research mean for the field?

Intramyocardial thioredoxin-1 gene therapy enhances angiogenic signaling, increases capillary density, and improves left ventricular functional recovery in diabetic rats following myocardial infarction. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate whether intramyocardial delivery of thioredoxin-1 gene therapy can reverse diabetes-mediated impairment of angiogenesis and improve myocardial function following myocardial infarction in diabetic rats.

Samson Mathews Samuel; Mahesh Thirunavukkarasu; Suresh Varma Penumathsa; Srikanth Koneru; Lijun Zhan; Gautam Maulik; P. R. Sudhakaran; Nilanjana Maulik

doi:10.1161/circulationaha.109.872481

March 2, 2010CirculationOpen Access

Thioredoxin-1 Gene Therapy Enhances Angiogenic Signaling and Reduces Ventricular Remodeling in Infarcted Myocardium of Diabetic Rats

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Key result

Intramyocardial Ad.Trx1 gene therapy improves LVEF by ~7 points in diabetic infarcted rats.

P<=0.05

Why the study?

Does intramyocardial Ad.Trx1 gene therapy improve myocardial angiogenesis, reduce ventricular remodeling, and preserve cardiac function in diabetic rats following myocardial infarction?

Key Points

To evaluate whether intramyocardial delivery of thioredoxin-1 gene therapy can reverse diabetes-mediated impairment of angiogenesis and improve myocardial function following myocardial infarction in diabetic rats.
Type 1 diabetic and nondiabetic rats underwent myocardial infarction and received intramyocardial injections of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1) or control vector (Ad.LacZ) immediately post-infarction.
Myocardial tissue was evaluated at 4 and 30 days post-infarction for oxidative stress, cell apoptosis, vascular density, and protein expression, with cardiac function assessed by echocardiography at 30 days.
Cultured human umbilical vein endothelial cells were transduced with Ad.Trx1 with or without the heme oxygenase-1 inhibitor tin protoporphyrin to examine angiogenic mechanisms in vitro.
Ad.Trx1 therapy significantly reduced cardiomyocyte apoptosis (204±13.1 vs 520±92.6 counts/100HPF) and endothelial cell apoptosis (208±32.8 vs 650±90.5 counts/100HPF) compared with untreated diabetic myocardial infarction.
Ad.Trx1 gene therapy significantly increased capillary density (2450±153 vs 1773±126 counts/mm2) and arteriolar density (30.6±1.5 vs 13.4±1.4 counts/mm2) in diabetic infarcted hearts.
Western blot analysis showed that Ad.Trx1 significantly elevated myocardial expression of thioredoxin-1 (2.8 fold), heme oxygenase-1 (3.2 fold), and vascular endothelial growth factor (2.2 fold) compared to untreated diabetic controls.

Structured PICO

Does intramyocardial Ad.Trx1 gene therapy improve myocardial angiogenesis, reduce ventricular remodeling, and preserve cardiac function in diabetic rats following myocardial infarction?

P

Population

Male Sprague-Dawley rats (300-325 gm) with streptozotocin-induced diabetes (blood glucose >=300 mg/dl) subjected to myocardial infarction and followed for up to 30 days.

I

Intervention

Intramyocardial administration of adenoviral vector encoding thioredoxin-1 (Ad.Trx1, 1 x 10^9 pfu in 100 uL PBS) at 4 different sites in the border zone surrounding the infarct immediately after myocardial infarction.

C

Comparator

Intramyocardial administration of control adenoviral vector encoding beta-galactosidase (Ad.LacZ, 1 x 10^9 pfu in 100 uL PBS) or untreated myocardial infarction controls (both diabetic and non-diabetic).

O

Outcome

Myocardial functional parameters measured by echocardiography 30 days after intervention (Ejection Fraction, Fractional Shortening, LVIDs, LVIDd, and E/A ratio) and myocardial angiogenesis (capillary and arteriolar density).surrogate

Main Result

Absolute Event Rate: 45.3% vs 38.5%

p-value: p=<=0.05

This preclinical study demonstrates for the first time that intramyocardial Trx1 gene therapy reverses diabetes-mediated impairment of angiogenesis and attenuates post-infarction ventricular remodeling via HO-1 and VEGF signaling.

Limitations

Preclinical animal model (streptozotocin-induced diabetic rats)
High post-MI mortality rate in diabetic animals (45-52%) precluded delayed gene delivery via a second thoracotomy
High mortality in diabetic animals after MI (45-52%) prevented delayed administration of gene therapy via a second thoracotomy
Small sample sizes per experimental group (n=3-5 per group)

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Implication

Hypothesis-generating for Trx1 gene therapy in diabetic post-MI models; leaves open translation to larger animals and humans.

Abstract

BACKGROUND: The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role. METHODS AND RESULTS: Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad.LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1-administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-beta, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase-alpha, in the Ad.Trx1-treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1-administered group compared with the diabetic myocardial infarction group. CONCLUSIONS: This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction.

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Cite This Study

Samuel et al. (2010) studied Myocardial infarction in streptozotocin-induced type 1 diabetic rats. Adenoviral vector encoding thioredoxin-1 (Ad.Trx1) gene therapy vs. Ad.LacZ (1 x 10^9 pfu) and untreated diabetic myocardial infarction controls was evaluated on Left ventricular ejection fraction at 30 days (p=<=0.05). Intramyocardial Ad.Trx1 gene therapy significantly improved left ventricular ejection fraction (45.3% vs 38.5%) and capillary density (2450 vs 1773 counts/mm2) at 30 days in diabetic infarcted rats.

synapsesocial.com/papers/6a7c9e8b0d0e3d593dba4b58 https://doi.org/10.1161/circulationaha.109.872481

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Thioredoxin-1 Gene Therapy Enhances Angiogenic Signaling and Reduces Ventricular Remodeling in Infarcted Myocardium of Diabetic Rats

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Thioredoxin-1 Gene Therapy Enhances Angiogenic Signaling and Reduces Ventricular Remodeling in Infarcted Myocardium of Diabetic Rats

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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