Impaired Ca(2+)-handling in HIF-1alpha(+/-) mice as a consequence of pressure overload

Area of Science:

• Cardiology
• Molecular Biology
• Physiology

Background:

• Hypoxia-inducible factor (HIF)-1 is vital for cellular adaptation to low oxygen.
• HIF-1alpha's role in cardiac hypertrophy and function under pressure overload is primarily linked to angiogenesis and hypertrophy.
• Previous understanding attributed HIF-1alpha's effects to challenged cardiac angiogenesis and hypertrophy.

Purpose of the Study:

• To investigate the specific role of HIF-1alpha in cardiac hypertrophy and function following sustained pressure overload.
• To determine if HIF-1alpha influences cardiac angiogenesis and hypertrophy development.
• To elucidate the mechanisms by which HIF-1alpha affects cardiac function under chronic pressure overload.

Main Methods:

• Utilized Hif-1alpha (+/+) and Hif-1alpha (+/-) mice subjected to transverse aortic constriction (TAC).
• Assessed left ventricular hypertrophy, cardiac function (fractional shortening), cardiac vessel density, and myocyte contractility.
• Analyzed intracellular Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) content in isolated myocytes.

Main Results:

• Both Hif-1alpha (+/+) and Hif-1alpha (+/-) mice exhibited similar degrees of left ventricular hypertrophy post-TAC.
• No significant differences in cardiac vessel density were observed between genotypes.
• Hif-1alpha (+/-) mice developed severe heart failure, characterized by reduced fractional shortening due to increased end-systolic diameter, impaired myocyte shortening, and altered calcium handling.

Conclusions:

• HIF-1alpha is critical for preserving cardiac function after chronic pressure overload, independent of its effect on cardiac hypertrophy.
• The protective effect of HIF-1alpha involves the modulation of cardiac calcium handling and contractility.
• Reduced HIF-1alpha levels compromise cardiac function through impaired calcium handling and myocyte contractility.