Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension.

Raffaele Altara,Fouad A Zouein,Romain Harmancey,George W Booz,Sean P Didion

doi:10.3389/fphar.2016.00436

Abstract

Signal transducer and activator of transcription 3 (STAT3) protects the heart from acute ischemic stress. However, the importance of STAT3 to the heart in chronic stress, such as hypertension, is not known. To study this, we used cardiomyocyte-targeted STAT3 knockout (KO) mice and Angiotensin II (ANG II) infusion by osmotic minipumps. After 4 weeks, ANG II induced similar cardiac hypertrophy in wild type (WT) and cardiac Cre-expressing control (CTRL) mice with no impairment of cardiac function. In contrast, STAT3 KO mice exhibited reduced contractile function but similar hypertrophy to CTRL mice. Ejection fraction and fractional shortening decreased by 22.5 and 27.3%, respectively. Since STAT3 has direct protective effects on mitochondrial function, we examined rates of glucose and oleate oxidation by isolated perfused hearts using a Langendorff system. Hearts of ANG II-treated STAT3 KO and CTRL mice had similar rates of oleate oxidation as saline-infused WT mice. Rates of glucose oxidation were similar between hearts of WT plus saline and CTRL plus ANG II mice; however, glucose oxidation was increased by 66% in hearts of ANG II-treated STAT3 KO mice. The ratio of maximal ATP yield from glucose to fatty acid oxidation was 21.1 ± 3.1 in hearts of ANG II-treated STAT3 KO mice vs. 12.6 ± 2.2 in hearts of ANG II-treated CTRL mice. Lactate production was also elevated in hearts of ANG II-treated STAT3 KO mice by 162% compared to ANG II-treated CTRL mice. Our findings indicate that STAT3 is important for maintaining contractile function and metabolic homeostasis in the hypertensive heart, and STAT3 deficiency promotes a switch toward glucose utilization.

Highlights

Heart Failure is a leading cause of death in the USA and developed world, and while survival after diagnosis has improved over time, the death rate remains high with ∼50% mortality within 5 years of diagnosis (Roger et al, 2012)
Contractile function was maintained by hearts of both wild type (WT) and Cre+ mice treated with Angiotensin II (ANG II) as assessed by Ejection fraction (EF) and fractional shortening (FS) (Supplementary Figure 2)
fatty acid oxidation (FAO) was not altered in the hearts of Signal transducer and activator of transcription 3 (STAT3) KO mice treated with ANG II for 28 days, these mice exhibited cardiac dysfunction at 14 days that persisted out to 28 days

Summary

Introduction

Heart Failure is a leading cause of death in the USA and developed world, and while survival after diagnosis has improved over time, the death rate remains high with ∼50% mortality within 5 years of diagnosis (Roger et al, 2012). Hypertension is the second most common risk factor for heart failure and accounts for ∼25% of heart failure cases (Kannel and Cobb, 1992). As many as 68% of heart failure cases are linked to hypertension and community-based studies indicate hypertension contributes to heart failure in 60% of patients (Yamasaki et al, 2003). Accumulating evidence indicates that preserving bioenergetics, including maintaining mitochondrial fatty acid oxidation (FAO), is critical for cardiac function and preventing both ischemic and non-ischemic heart failure (Abdurrachim et al, 2015; Kundu et al, 2015). Hypertension-induced cardiac hypertrophy is associated with a reduction in FAO and increased reliance on anaerobic glycolysis (Kolwicz et al, 2012). The basis for the metabolic reprogramming of the hypertrophied and early stage failing heart is not understood, but seems to involve both transcriptional and mitochondrial post-transcriptional events (Lai et al, 2014)

Results

Discussion

Conclusion