Ovarian Cancer (OC) is recognized as the most lethal gynecologic malignancy, characterized by numerous genetic mutations that trigger uncontrolled cellular growth and replication. Emerging evidence suggests that non-coding RNAs including miRNAs and lncRNAs significantly influence OC through their multiple roles including tumor initiation, progression, metastasis, immune evasion, and chemoresistance, making them promising diagnostic markers and therapeutic targets. The primary approach to treating OC typically involves cytoreductive surgery followed by chemotherapy. However, the chemotherapeutic agents, particularly the anthracyclines such as doxorubicin (DOX), are known for their cardiotoxic effects, which can range from acute to chronic, potentially leading to heart failure and death. To enhance the overall treatment response and to minimize cardiotoxicity, alternative strategies have been explored. These include the use of liposomal doxorubicin (DOXIL) as a substitute for DOX, various radiotherapies, immunotherapies, and the co-administration of angiotensin-converting enzyme inhibitors and/or beta-blockers. Phosphodiesterase-5 inhibitors (PDE5i) have also demonstrated efficacy in reducing cardiotoxicity linked to cancer treatments and in promoting apoptosis in cancer cells across multiple cancer types. Although there is no current clinical trial directly examining the impact of PDE5i on reducing cardiotoxicity in OC, however emerging therapies such as Withaferin A, PARP inhibitors, and nanoparticle combination therapy show promise. Additional research is essential to develop treatments that are both effective against OC and less harmful to the heart.

Background: Dysregulation of microRNAs (miRNAs), including the miR-17-92 cluster, has been implicated in the pathogenesis of heart disease and related conditions, such as diabetes, hypertension, and ischemia/reperfusion (I/R) injury. Aberrancies in bioactive sphingolipid metabolism, specifically ceramide (CER), contribute to diabetic cardiomyopathy, where induction of ceramide synthases (CerS) predicts elevated risk of cardiovascular complications. This study investigates whether miR-17-92 can mitigate cardiomyocyte death following simulated ischemia/reoxygenation (SI/RO) under diabetic condition by targeting CerS. Methods & Results: Isolated cardiomyocytes from adult tamoxifen-inducible cardiac-specific miR-17-92 knock-in (KI) and knock-out (KO) male mice were subjected to SI for 40 minutes and RO for 1 hour with high glucose (25 mM). Cardiomyocytes from miR-17-92 KO mice exhibited significantly higher cell death (assessed by trypan blue staining) and apoptosis (assessed by TUNEL staining) post-SI/RO compared to wild type, while cell death was markedly reduced in miR-17-92 KI cardiomyocytes under hyperglycemic conditions. Human cardiomyocyte cells, AC16, were transfected with miR-20a mimic (a member of the miR-17-92 cluster) and incubated with high glucose (25 mM). After 24 hours, cells were exposed to SI (4 hours) followed by 24 hours of RO in high glucose conditions. Overexpression of miR-20a (confirmed by Real-time PCR) protected AC16 cardiomyocytes from SI/RO injury in both normal and hyperglycemic conditions. Western blot analysis and Real-time PCR confirmed that overexpression of miR-20a in AC-16 cells reduced expression of sphingolipid biosynthesis enzymes, ceramide synthase 6 (CerS6) and sphingomyelin synthase 2 (SMS2) after SI/RO under hyperglycemic condition. Conclusion: This study demonstrated that overexpression of miR-20, a member of miR-17-92 cluster, protects cardiomyocytes from ischemia/reperfusion injury by downregulating CerS6 and SMS2, thereby reducing lipotoxicity and pro-apoptotic signaling. These findings suggest that miR-17-92 as a potential therapeutic target for mitigating myocardial infarction in diabetic patients. This work was supported in part by grants from the National Institutes of Health RO1HL134366 (A.D.) and RO1HL158951 (A.D.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Cardiovascular diseases, including acute myocardial infarctions, heart failure, hypertension, adverse cardiac remodeling, hypertrophy, atherosclerosis, and coronary artery disease, continue to lead to global mortality rates. Annual global cancer mortality rates follow closely behind, emphasizing the need to develop novel therapeutic approaches. MicroRNAs (miRNAs), a class of short non-coding RNAs, regulate cascades of signaling pathways and their downstream targets, exerting control over numerous biological processes. Dysregulation in specific miRNAs is linked to various pathogenesis, including cancer and cardiovascular disease. Among these miRNAs, the miRNA-17-92 cluster plays versatile roles at the nexus of critical physiological and pathological processes, including cardiac diseases and malignancy. This review aimed to provide a holistic analysis of the current progress in identifying, developing, and utilizing the miRNA-17-92 cluster to combat cardiovascular diseases and cancer. The members of the miRNA-17-92 cluster exert control over numerous cellular pathways that regulate, suppress, and promote various aspects of cardiomyocyte differentiation, regeneration, and aging. Certain pathways controlled by the cluster are protective when properly expressed. Others can propagate unchecked cardiovascular disease progression and mortality due to poorly controlled over/under-regulation. Similarly, the miRNA-17-92 cluster plays critical regulatory roles in the occurrence, metastasis, and prognosis of multiple cancers, which may allow the cluster to serve as diagnostic and prognostic biomarkers of malignancy. This review provides a brief overview of the multifaceted roles of the miRNA-17-92 cluster to deliver some insight into the development of novel targeted therapeutics for cardiovascular diseases and cancer via controlling the expression of specific subsets within this cluster. Additionally, this review systematically summarizes the established molecular mechanisms of the miRNA-17-92 cluster and its therapeutic potential in dual pathological contexts, cardiovascular diseases, and cancer.

BACKGROUND:The significance of autonomic dysfunction in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. OBJECTIVES:Utilizing a novel "dual stressor" provocative challenge combining exercise with premature ventricular contraction (PVCs), the authors characterized the functional and molecular mechanisms of cardiac autonomic (cardiac autonomic nervous system) remodeling in a PVC-CM animal model. METHODS:In 15 canines (8 experimental, 7 sham), we implanted pacemakers and neurotelemetry devices and subjected animals to 12 weeks of bigeminal PVCs to induce PVC-CM. Sympathetic nerve activity (SNA), vagal nerve activity (VNA), and heart rate were continuously recorded before, during, and after treadmill exercise challenge with and without PVCs, at baseline and after development of PVC-CM. Western blot and enzyme-linked immunosorbent assay were used to evaluate molecular markers of neural remodeling. RESULTS:Exercise triggered an increase in both SNA and VNA followed by late VNA withdrawal. With PVCs, the degree of exercise-induced SNA augmentation was magnified, whereas late VNA withdrawal became blunted. After PVC-CM development, SNA was increased at rest but failed to adequately augment during exercise, especially with PVCs, coupled with impaired VNA and heart rate recovery after exercise. In the remodeled cardiac autonomic nervous system, there was widespread sympathetic hyperinnervation and elevated transcardiac norepinephrine levels but unchanged parasympathetic innervation, indicating sympathetic overload. However, cardiac nerve growth factor was paradoxically downregulated, suggesting an antineurotrophic counteradaptive response to PVC-triggered sympathetic overload. CONCLUSIONS:Sympathetic overload, sympathetic dysfunction, and parasympathetic dysfunction in PVC-CM are unmasked by combined exercise and PVC challenge. Reduced cardiac neurotrophic factor might underlie the mechanisms of this dysfunction. Neuromodulation therapies to restore autonomic function could constitute a novel therapeutic approach for PVC-CM.

BACKGROUND:The mechanisms underlying postoperative atrial fibrillation (POAF) remain unclear. OBJECTIVES:The aim of this study was to test the hypothesis that targeted chemical ganglionated plexi (GP) modulation of all major left atrial-pulmonary vein GP using novel nanoformulated calcium chloride (nCaCl2) can reverse postoperative neuroelectrical remodeling by suppressing vagosympathetic nerve activity and the localized inflammatory process, both critical substrates of POAF. METHODS:In a novel canine model of POAF with serial thoracopericardiotomies, sympathetic nerve activity (SNA), vagal nerve activity (VNA) and GP nerve activity (GPNA) were recorded; spontaneous and in vivo AF vulnerability were assessed; and atrial and circulating inflammatory markers and norepinephrine (NE) were measured to determine the neuroelectrical remodeling that promotes POAF and its subsequent modulation with nCaCl2 GP treatment (n = 6) vs saline sham controls (n = 6). RESULTS:The first 3 postpericardiotomy weeks demonstrated increased plasma C-reactive protein (P = 0.034) and NE (P = 0.033), decreased atrial effective refractory period (P = 0.002), and increased AF vulnerability (P = 0.0008). Subsequent nCaCl2 GP treatment reversed atrial effective refractory period remodeling 6 weeks later (P < 0.001) and decreased AF vulnerability (P = 0.0002) and spontaneous AF burden (P = 0.03). nCaCl2 GP treatment acutely (3 days) and chronically (6 weeks) suppressed GPNA (P = 0.008 and P = 0.04), SNA (P = 0.048 and P = 0.041), and VNA (P = 0.041 and P = 0.046) and increased mean RR interval (P = 0.046 and P = 0.034). In sham controls, the opposite changes occurred (increased GPNA [P = 0.035 and P = 0.02], SNA [P = 0.048 and P = 0.042], and VNA [P = 0.041 and P = 0.042] and decreased mean RR interval [P = 0.041 and P = 0.046]). Plasma NE (P = 0.044), left atrial interleukin-6 (P = 0.008), nerve growth factor (P < 0.001), and sympathetic nerve levels (P < 0.001) were reduced, along with apoptosis of GP neurons in the nCaCl2 GP group. CONCLUSIONS:Targeted GP modulation with nCaCl2 durably suppresses POAF by inducing apoptosis of GP neurons and inhibiting GP and vagosympathetic nerve activity. This exerts a localized anti-inflammatory effect to reverse the proarrhythmic neural-electrical remodeling following thoracopericardiotomy without myocardial damage or compensatory neural regrowth.

Cardiac Kv4.3 channels contribute to the transient outward K+ current, Ito, during early repolarization of the cardiac action potential. Two different isoforms of Kv4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both Kv4.3 isoforms to explore their potential for isoform-specific therapy. Kv4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two Kv4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked Kv4.3 L by 77 ± 2% and Kv4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (Kv4.3 L) and 35 ± 4% (Kv4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in Kv4.3 protein expression. Carvedilol inhibited Kv4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on Kv4.3. Blockade of repolarizing Kv4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in the heart of diabetic rabbits following I/R injury with/without RAPA treatment to identify differentially expressed (DE) miRNAs and their predicted targets of lncRNAs/mRNAs. Results showed that among the total of 806 unique miRNAs targets, 194 miRNAs were DE after I/R in diabetic rabbits. Specifically, eight miRNAs, including miR-199a-5p, miR-154-5p, miR-543-3p, miR-379-3p, miR-379-5p, miR-299-5p, miR-140-3p, and miR-497-5p, were upregulated and 10 miRNAs, including miR-1-3p, miR-1b, miR-29b-3p, miR-29c-3p, miR-30e-3p, miR-133c, miR-196c-3p, miR-322-5p, miR-499-5p, and miR-672-5p, were significantly downregulated after I/R injury. Interestingly, RAPA treatment significantly reversed these changes in miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated the participation of miRNAs in the regulation of several signaling pathways related to I/R injury, including MAPK signaling and apoptosis. Furthermore, in diabetic hearts, the expression of lncRNAs, HOTAIR, and GAS5 were induced after I/R injury, but RAPA suppressed these lncRNAs. In contrast, MALAT1 was significantly reduced following I/R injury, with the increased expression of miR-199a-5p and suppression of its target, the anti-apoptotic protein Bcl-2. RAPA recovered MALAT1 expression with its sponging effect on miR-199-5p and restoration of Bcl-2 expression. The identification of novel targets from the transcriptome analysis in RAPA-treated diabetic hearts could potentially lead to the development of new therapeutic strategies for diabetic patients with myocardial infarction.

Background: We previously demonstrated that a novel combination therapy with the phosphodiesterase 5 (PDE5) inhibitor (sildenafil, Sild) and mTOR inhibitor (rapamycin, Rapa) potentiates doxorubicin (DOX)-induced breast cancer cell killing, but attenuates cardiotoxicities. However, it remains unclear whether there are any factors released from cancer cells treated with DOX that contribute to the injury in cardiomyocytes, which can be modified by Sild and Rapa in combination. Therefore, we designed experiments using spheroid cultures of breast cancer and human AC-16 cardiomyocytes to determine the role of endogenously released factors following treatment with DOX. Methods & Results: Spheroid cultures of breast cancer MDA-MB-231 cells were treated with DOX (1 μμ), and/or Sild (10 μμ) and Rapa (100 nμ) for 48 hours. The medium was replaced and spheroids were further incubated for 48 hours in the fresh medium. Thereafter, the AC-16 cardiomyocytes were treated with the medium from drugs-treated spheroids for 48 hours. Our results showed that treatment with DOX and/or Sild and Rapa was highly effective in reducing the size of spheroids as compared to the control ( Fig. A ). Moreover, Western blots showed that p-mTOR/mTOR and p-S6/S6 were induced and p-AKT/AKT was suppressed after DOX treatment in cancer cells, which were normalized following treatment with Sild and Rapa ( Fig. B ). The medium from DOX-treated spheroids caused increase of cardiomyocytes death as assessed by trypan blue exclusion assay, which was attenuated by co-treatment with the medium from Sild and Rapa treated spheroids ( Fig. C ). Conclusion: These results suggest that cardiotoxicity of chemotherapeutic agents could be partly contributed by the endogenously released unknown factors from tumors, which can be modulated by a novel combination treatment with Sild and Rapa via regulating mTOR-signaling pathways.

Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium–glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

Robust activation of mTOR (mammalian target of rapamycin) signaling in diabetes exacerbates myocardial injury following lethal ischemia due to accelerated cardiomyocyte death with cardiac remodeling and inflammatory responses. We examined the effect of rapamycin (RAPA, mTOR inhibitor) on cardiac remodeling and inflammation following myocardial ischemia/reperfusion (I/R) injury in diabetic rabbits. Diabetic rabbits (DM) were subjected to 45 min of ischemia and 10 days of reperfusion by inflating/deflating a previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before the onset of reperfusion. Post-I/R left ventricular (LV) function was assessed by echocardiography and fibrosis was evaluated by picrosirius red staining. Treatment with RAPA preserved LV ejection fraction and reduced fibrosis. Immunoblot and real-time PCR revealed that RAPA treatment inhibited several fibrosis markers (TGF-β, Galectin-3, MYH, p-SMAD). Furthermore, immunofluorescence staining revealed the attenuation of post-I/R NLRP3-inflammasome formation with RAPA treatment as shown by reduced aggregation of apoptosis speck-like protein with a caspase recruitment domain and active-form of caspase-1 in cardiomyocytes. In conclusion, our study suggests that acute reperfusion therapy with RAPA may be a viable strategy to preserve cardiac function with the alleviation of adverse post-infarct myocardial remodeling and inflammation in diabetic patients.

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.

Phosphodiesterase 5 (PDE5) is an enzyme that catalyzes the degradation of cGMP to its inactive form, 5′-GMP. The inhibition of PDE5 leads to the increase in bioavailability of cGMP which exerts its downstream signaling effects through the activation of protein kinase G (PKG). The dysregulation of cGMP-PKG signaling cascade plays a critical role in the pathology of several cardiovascular disorders. PDE5 inhibitors including sildenafil and tadalafil are widely prescribed drugs for the treatment of erectile dysfunction and pulmonary hypertension in patients. In the pre-clinical setting, treatment with PDE5 inhibitors protect against several cardiovascular pathologies including ischemia/reperfusion (I/R) injury, heart failure, pressure overload-induced hypertrophy, and cardiomyopathy associated with type 2 diabetes and metabolic syndrome. Mechanistic studies reveal that nitric oxide (NO)-cGMP-PKG signaling driven multiple signaling pathways are involved in protection against most of these pathologies. Moreover, the PDE5 inhibitors generate other gasotransmitters including hydrogen sulfide, carbon monoxide in addition to NO that may play a critical role in cardioprotection.

The mechanistic/mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase (PI3K) related kinase family, integrates intracellular and environmental cues that coordinate a diverse set of cellular/tissue functions, such as cell growth, proliferation, metabolism, autophagy, apoptosis, longevity, protein/lipid/nucleotide synthesis, and tissue regeneration and repair [...].