Abstract
The heart is innervated by the sympathetic, parasympathetic and sensory nerves. The cardiac sympathetic nervous system plays an important role in the regulation of cardiac functions, such as increasing heart rate, myocardial contraction and conduction velocity.
A change in sympathetic nerve fiber density leads to an imbalance that results in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia and infarction, cardiac dysfunction and arrhythmias, sudden cardiac death and heart failure. This project uses a transgenic mouse model with a conditional deletion of Hif1a (Hif1aCKO) in sympathetic neurons.
We evaluated how the diabetic environment in combination with HIF-1α dysregulation affects the cardiac sympathetic system and heart function. Our results show that the two- month-exposure to the diabetic environment leads to the reduction of sympathetic innervation in the hearts of Hif1aCKO mice; the branching and thickness of innervation, together with the density of sympathetic neurons are affected.
Additionally, we identified aberrant structural remodeling of the myocardium, vasculature changes, macrophage infiltration, and increased expression of cardiac injury markers in our diabetic Hif1aCKO mice compared with non-diabetic mice. Compared to the control, RNA sequencing of neurons isolated from Hif1aCKO sympathetic ganglia show differentially expressed genes associated with sympathetic neurons, heart function, and hypoxia.
We demonstrated that the elimination of Hif1a in the sympathetic nervous system in combination with diabetes results in changed transcriptome, compromised cardiac innervation, worsened heart function, and adverse myocardial remodeling.