Synergistic Effects of Low-Frequency Ultrasound and Therapeutic Agents on Endothelial and Renal Cells: Emphasis on Cell Functionality, Oxidative Stress, and Inflammatory Markers
Ieva Čiapienė1, Joris Vėžys2, Vaiva Lesauskaitė1
1Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania.
Insights
Low-frequency ultrasound (LFU) enhances angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) effects on endothelial cells, improving nitric oxide (NO) production and reducing inflammation. However, LFU combined with dexamethasone shows variable effects on renal cells.
Area of Science:
- Cardiovascular Research
- Biomedical Engineering
- Pharmacology
Background:
- Ischemic heart disease and coronary microvascular dysfunction (CMD) are leading global health issues.
- Endothelial dysfunction is a key factor in CMD, impacting vascular tone and inflammation.
- Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are crucial for vascular health, with potential synergy with therapeutic ultrasound.
Purpose of the Study:
- To investigate the combined effects of low-frequency ultrasound (LFU) and pharmacological agents (captopril, losartan, dexamethasone) on the ACE axis and inflammation.
- To assess the impact of LFU on endothelial and renal cell function, redox signaling, and gene expression.
- To determine if LFU enhances the therapeutic efficacy of ACE inhibitors and ARBs.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) and RPTEC/TERT1 renal cells were treated with captopril, losartan, or dexamethasone, with or without LFU.
- Cell viability, wound healing, nitric oxide (NO), and reactive oxygen species (ROS) assays were performed.
- Quantitative PCR (qPCR) analyzed gene expression related to the ACE axis, inflammation, and cell function.
Main Results:
- LFU combined with captopril or losartan improved HUVEC viability, wound healing, and NO production.
- Losartan with LFU enhanced viability and wound healing in renal cells; dexamethasone with LFU increased ROS.
- LFU modulated inflammatory gene expression (VCAM-1, ICAM-1, PTGS2) and ACE axis-related genes (CYP4F2, SGLT2, GGT1) in a drug- and cell-dependent manner.
Conclusions:
- LFU potentiates the beneficial effects of RAS inhibitors on endothelial cells by increasing NO and reducing oxidative stress.
- The combination of LFU and dexamethasone may have complex or cytotoxic effects on renal cells.
- LFU demonstrates anti-inflammatory potential and can modulate drug efficacy, suggesting a role in enhancing cardiovascular therapies.
Abstract:
Background: Ischemic heart disease remains the leading cause of death worldwide, with coronary microvascular dysfunction (CMD) as a key complication after ST-elevation myocardial infarction (STEMI). Endothelial dysfunction contributes to CMD, impairing vascular tone and increasing inflammation. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) aid vascular health, their efficacy may improve with therapeutic ultrasound, which enhances drug delivery and endothelial response. This study explores the combined effects of ultrasound and pharmacological treatment on the ACE axis and inflammation in endothelial and renal cells. Methods: Human umbilical vein endothelial cells (HUVECs) and human renal proximal tubular epithelial cell line RPTEC/TERT1 were treated with captopril, losartan, and dexamethasone, alone or combined with low-frequency ultrasound (LFU). Cell viability and wound-healing assays assessed cellular function, while nitric oxide (NO) and reactive oxygen species (ROS) assays were used to evaluate redox signaling. Gene expression related to the ACE axis, inflammation, and vascular and renal cell function was analyzed via qPCR. Results: Captopril and losartan combined with LFU improved endothelial cell viability, wound healing, and NO production at various concentrations, whereas only losartan with LFU enhanced cell viability and wound healing in renal cells. Dexamethasone with LFU increased ROS levels and had variable effects on RPTEC/TERT1 cell survival. Gene expression analysis showed that LFU alone reduced pro-inflammatory markers VCAM-1, ICAM-1, and PTGS2 in captopril-treated HUVECs and similarly affected CYP4F2 in losartan-treated HUVECs. LFU also decreased PTGS2 expression at higher dexamethasone concentrations. In RPTEC/TERT1 cells, LFU alone did not impact SGLT2 or GGT1 expression, but captopril with LFU downregulated GGT1, and dexamethasone with LFU upregulated SGLT2 at higher concentrations. Conclusions: This study demonstrates that LFU enhances the effects of RAS inhibitors by promoting NO synthesis and reducing oxidative stress, while its combination with dexamethasone may have variable, potentially cytotoxic effects on renal cells. Gene expression patterns suggest LFU's anti-inflammatory potential and its role in modulating drug efficacy.
