RNA therapeutics for cardiovascular disease.

PURPOSE OF REVIEW: The development of mRNA vaccines against coronavirus disease 2019 has brought worldwide attention to the transformative potential of RNA-based therapeutics. The latter is essentially biological software that can be rapidly designed and generated, with an extensive catalog of applications. This review aims to highlight the mechanisms of action by which RNA-based drugs can affect specific gene targets and how RNA drugs can be employed to treat cardiovascular disease, with the focus on the therapeutics being evaluated in clinical trials. The recent advances in nanotechnology aiding the translation of such therapies into the clinic are also discussed. RECENT FINDINGS: There is a growing body of studies demonstrating utility of RNA for targeting previously 'undruggable' pathways involved in development and progression of cardiovascular disease. Some challenges in RNA delivery have been overcome thanks to nanotechnology. There are several RNA-based drugs to treat hypercholesterolemia and myocardial infarction which are currently in clinical trials. SUMMARY: RNA therapeutics is a rapidly emerging field of biotherapeutics based upon a powerful and versatile platform with a nearly unlimited capacity to address unmet clinical needs. These therapeutics are destined to change the standard of care for many diseases, including cardiovascular disease.

Proton Pump Inhibitors Accelerate Endothelial Senescence.

RATIONALE: Proton pump inhibitors (PPIs) are popular drugs for gastroesophageal reflux, which are now available for long-term use without medical supervision. Recent reports suggest that PPI use is associated with cardiovascular, renal, and neurological morbidity. OBJECTIVE: To study the long-term effect of PPIs on endothelial dysfunction and senescence and investigate the mechanism involved in PPI-induced vascular dysfunction. METHODS AND RESULTS: Chronic exposure to PPIs impaired endothelial function and accelerated human endothelial senescence by reducing telomere length. CONCLUSIONS: Our data may provide a unifying mechanism for the association of PPI use with increased risk of cardiovascular, renal, and neurological morbidity and mortality.

Methylated arginine analogues: their potential role in atherosclerosis and cognition using the poloxamer-407-induced mouse model of dyslipidemia.

An experimental mouse model of dyslipidemia and atherosclerosis was utilized to study the generation of methylarginines in vivo, as well as any potential behavioral changes in mice associated with the production of excess methylarginines. Following 14 weeks of poloxamer 407 treatment, mice developed atherosclerosis and the plasma concentrations of monomethylarginine and asymmetric dimethylarginine were found to be significantly greater than corresponding concentrations in control mice. This finding may have contributed to the development of aortic atherosclerotic lesions in poloxamer-treated mice by interfering with nitric oxide availability and, hence, normal function of vascular endothelium. Poloxamer-407-treated mice also showed a significant decrease in locomotor and exploratory activity, together with signs of emotional stress and anxiety relative to controls. Passive avoidance testing to assess learning and memory provided suggestive evidence that poloxamer-treated mice could potentially be characterized as having undergone a disruption in the process of forgetting about an aversive event, specifically, a foot shock, when compared with control mice. Thus, it is also suggested that the increase in both plasma monomethylarginine and asymmetric dimethylarginine in poloxamer-407-treated mice may somehow influence learning and memory, because endothelial dysfunction caused by reduced nitric oxide availability has been hypothesized to negatively influence cognitive function.

The influence of acute renal injury on arginine and methylarginines metabolism.

Arginine (ARG) and its methylated analogs (methylarginines) are the crucial regulators of nitric oxide (NO) bioavailability. ARG is the substrate for NO synthesis, whereas monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA) are potent inhibitors. Symmetric dimethylarginine (SDMA) does not interfere with NO synthesis, but competes with ARG for the intracellular transport. The kidneys play the major role in ARG and methylarginines metabolism. They synthesize ARG de novo and eliminate methylarginines by excretion into urine and also by enzyme dimethylarginine dimethylaminohydrolase (DDAH) degrading only ADMA and MMA. Acute renal injury (ARI) is known to be accompanied by reduced NO production in the body. This study aimed to investigate the influence of ARI on ARG and methylarginines metabolism, and to establish the relationship between disturbances in the latter and reduced NO bioavailability in ARI. The rhabdomyolysis-related ARI model in rats was used. ARI reduced renal synthesis of ARG and its level in circulation as well as renal DDAH activity. However, ADMA did not accumulate because of its increased urinary excretion. Whole-body production of SDMA was increased significantly, whereas whole-body metabolism of MMA did not change. ARG and methylarginines content in renal tissue was decreased. Moreover, the balance between the substrate and inhibitors for NO synthesis was changed in favor of the inhibitors in renal tissue as well as in blood, and daily urinary excretion of NO metabolites was significantly decreased. Thus, ARI provokes severe disturbances in ARG and methylarginines metabolism that results in reduced NO bioavailability in the kidney and the whole body.

mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration.

mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target "undruggable" diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration.

The Limitless Future of RNA Therapeutics.

Recent advances in the generation, purification and cellular delivery of RNA have enabled development of RNA-based therapeutics for a broad array of applications. RNA therapeutics comprise a rapidly expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. In this review we discuss general concepts of different classes of RNA-based therapeutics, including antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and messenger RNA. Furthermore, we provide an overview of the RNA-based therapies that are currently being evaluated in clinical trials or have already received regulatory approval. The challenges and advantages associated with use of RNA-based drugs are also discussed along with various approaches for RNA delivery. In addition, we introduce a new concept of hospital-based RNA therapeutics and share our experience with establishing such a platform at Houston Methodist Hospital.

Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery.

Activation of the vascular endothelium is characterized by increased expression of vascular adhesion molecules and chemokines. This activation occurs early in the progression of several diseases and triggers the recruitment of leukocytes. Inspired by the tropism of leukocytes, we investigated leukocyte-based biomimetic nanoparticles (i.e., leukosomes) as a novel theranostic platform for inflammatory diseases. Methods: Leukosomes were assembled by combining phospholipids and membrane proteins from leukocytes. For imaging applications, phospholipids modified with rhodamine and gadolinium were used. Leukosomes incubated with antibodies blocking lymphocyte function-associated antigen 1 (LFA-1) and CD45 were administered to explore their roles in targeting inflammation. In addition, relaxometric assessment of NPs was evaluated. Results: Liposomes and leukosomes were both spherical in shape with sizes ranging from 140-170 nm. Both NPs successfully integrated 8 and 13 µg of rhodamine and gadolinium, respectively, and demonstrated less than 4% variation in physicochemical features. Leukosomes demonstrated a 16-fold increase in breast tumor accumulation relative to liposomes. Furthermore, quantification of leukosomes in tumor vessels demonstrated a 4.5-fold increase in vessel lumens and a 14-fold increase in vessel walls. Investigating the targeting mechanism of action revealed that blockage of LFA-1 on leukosomes resulted in a 95% decrease in tumor accumulation. Whereas blockage of CD45 yielded a 60% decrease in targeting and significant increases in liver and spleen accumulation. In addition, when administered in mice with atherosclerotic plaques, leukosomes exhibited a 4-fold increase in the targeting of inflammatory vascular lesions. Lastly, relaxometric assessment of NPs demonstrated that the incorporation of membrane proteins into leukosomes did not impact the r1 and r2 relaxivities of the NPs, demonstrating 6 and 30 mM-1s-1, respectively. Conclusion: Our study demonstrates the ability of leukosomes to target activated vasculature and exhibit superior accumulation in tumors and vascular lesions. The versatility of the phospholipid backbone within leukosomes permits the incorporation of various contrast agents. Furthermore, leukosomes can potentially be loaded with therapeutics possessing diverse physical properties and thus warrant further investigation toward the development of powerful theranostic agents.

How May Proton Pump Inhibitors Impair Cardiovascular Health?

Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.

Local Inhibition of Macrophage and Smooth Muscle Cell Proliferation to Suppress Plaque Progression.

Atherosclerosis is a complex process responsible for a major burden of cardiovascular morbidity and mortality. Macrophages and smooth muscle cells (SMCs) are abundant within atherosclerotic plaques. This review discusses the role of macrophages and SMCs in plaque progression and provides an overview of nanoparticle-based approaches and other current methods for local targeting of atherosclerotic plaques.

Endothelium-Derived Nitric Oxide as an Antiatherogenic Mechanism: Implications for Therapy.

Endothelium-derived nitric oxide (eNO) is a multifunctional signaling molecule critically involved in the maintenance of metabolic and cardiovascular homeostasis. In addition to its role as a potent endogenous vasodilator, eNO suppresses key processes in vascular lesion formation and opposes atherogenesis. This review discusses eNO as an antiatherogenic molecule and highlights factors that influence its bioavailability and therapeutic approaches to restore or enhance its levels.