Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy

Abstract

Background An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals. Methods Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses. Results We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium. Conclusions We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.

Identification of diagnostic model in heart failure with myocardial fibrosis and conduction block by integrated gene co-expression network analysis

“…HIF1A is an important transcription factor that plays a key role in the adaptive response of cells to low-oxygen environments. It is found that abnormal expression of HIF1A in the sympathetic nervous system affects myocardial collagen deposition, ECM formation, and myocardial fibrosis in diabetic cardiomyopathy [ 50 ]. HIF1A has been shown to enhance the activation of cardiac fibroblasts by upregulating the expression of specific genes associated with ECM formation [ 51 ].…”

Unraveling the role of HIF-1α in sepsis: from pathophysiology to potential therapeutics—a narrative review

“…On the macro-level, HIF-1α plays a pivotal role in enhancing the myocardial tissue's tolerance to ischemic injury [ 8 ]. Diabetic mice deficient in HIF-1α exhibit significant cardiac contractile dysfunction, increased cardiac sympathetic innervation, and subsequent myocardial structural remodeling [ 38 ]. The expression of HIF-1α in myeloid cells provides protection during ischemia and reperfusion injury in the heart [ 39 ].…”

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

“…Plates were frozen immediately on dry ice and stored at −80°C. The total time from euthanasia to cell collection was ∼3 h. The RNA library preparation, RNA sequencing (RNA-seq), and data processing were performed as described previously (27). Briefly, the NEBNext single-cell low-input RNA library prep kit for Illumina (#E6420, New England Biolabs) was used for library generation at the Gene Core Facility (Institute of Biotechnology CAS, Czechia), and the libraries were sequenced on an Illumina NextSeq 500 next-generation sequencer with NextSeq 500/550 High Output kit 75 cycles (Illumina #200024906) at the Genomics and Bioinformatics Core Facility (Institute of Molecular Genetics CAS, Czechia).…”

“…Changes in cardiac sympathetic innervation and sympathetic system activity are implicated in many pathologies in adults, including sudden cardiac death, myocardial ischemia, cardiac death, hypertension, diabetic heart disease, and heart failure ( 25 , 26 ). Emerging evidence suggests that many of the sympathetic dysfunctions in various pathological heart conditions have a developmental origin ( 19 , 20 , 27 , 28 ). Using conditional deletion of oxygen-sensitive subunit HIF-1α, we previously revealed a key role for the transcription factor hypoxia-inducible factor 1 (HIF-1) in the development of sympathetic neurons and sympathetic innervation of the developing heart and its negative effects on heart function in adults ( 29 ).…”