MicroRNAs, Hypertension and End Organ Damage in Humans

Study 1) Profiling of microRNAs in plasma of patients with hypertension complicated or not by metabolic syndrome or chronic kidney disease Hypertension (HTN) or high blood pressure is associated with subclinical target organ damage such as cardiac, vascular and kidney injury, which may lead to complications and death. In this study, we investigated circulating microRNAs as biomarkers of target organ damage in HTN patients. We profiled circulating microRNAs by RNA sequencing in platelet-poor plasma of normotensive subjects and patients with HTN complicated or not by metabolic syndrome (MetS) or chronic kidney disease (CKD) (n=15 each group). Differentially expressed microRNAs were identified with a threshold of false discovery rate <0.1. Differentially expressed microRNAs were identified uniquely to associate with HTN (8), MetS (1) or CKD (13), and 8 were similarly differentially expressed in different groups. This study identified the association of differentially expressed circulating microRNAs with target organ damage in HTN patients, which could have some pathophysiological and therapeutic implications. Study 2) Profiling of microRNAs in gluteal subcutaneous small arteries of patients with hypertension complicated or not by chronic kidney disease Hypertension (HTN) is associated with vascular damage characterized by endothelial dysfunction and vascular remodeling and stiffening, which contributes to kidney injury leading to chronic kidney disease (CKD). MicroRNAs are short non-coding RNAs which repress/degrade target mRNAs. The microRNA role in vascular injury in HTN remains unclear. In this study, we aimed to identify differentially expressed microRNAs in small arteries of patients with HTN associated or not with CKD, in order to shed light on the pathophysiological molecular mechanisms. Normotensive subjects and HTN patients associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from subcutaneous gluteal biopsies, RNAs were extracted, and small and total RNA sequencing was performed by Illumina HiSeq-2500. Differentially expressed genes were identified with a P<0.05 and fold change (FC) >1.3. Differentially expressed microRNAs and mRNAs were identified uniquely to associate with HTN (microRNAs: 10, mRNAs: 68), CKD (microRNAs: 68, mRNAs: 395), and both groups (microRNAs: 2, mRNAs: 32). This study identified differentially expressed microRNAs and mRNAs in small arteries with target organ damage in HTN, which could have some pathophysiological and therapeutic implications. ]]> INCLUSION CRITERIAHypertensive subjects (HTN) were recruited in the study on the basis of systolic blood pressure (BP) >135 mmHg or diastolic BP of 85-115 mmHg with BpTRU BPM-300 or treatment with anti-hypertensive medication for at least 6 months; MetS group included HTN as above and at least 2 of the following criteria defined in National Cholesterol Education Program (NCEP): central obesity: waist circumference ≥102 cm or 40 inches (male), ≥88 cm or 36 inches (female), dyslipidemia: triglycerides (TG) ≥ 1.7 mmol/L (150 mg/dl), high density lipoprotein cholesterol (HDL-C) male <40 mg/dL (1.03 mmol/L), female < 50 mg/dL (1.29 mmol/L), or treatment with cholesterol lowering drug, fasting plasma glucose ≥6.1 mmol/L (110 mg/dl) or treated with hypoglycemic drugs; CKD group included HTN as above and associated with hypertensive nephropathy, defined as alteration of glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, after exclusion of other causes of CKD; and normotensive subjects without HTN, MetS or CKD. Subjects enrolled were 33 to 78 years old. The patients were followed in the Kidney Treatment Center and in the Cardiovascular Prevention Center of the Jewish General Hospital. EXCLUSION CRITERIA Subjects meeting any one of the following criteria were excluded: myocardial infarction within the 6 months; percutaneous coronary angioplasty or coronary artery bypass surgery within last 6 months; clinically significant atrioventricular (AV) conduction disturbances or arrhythmias (e.g. second- or third-degree AV block, sick-sinus syndrome or clinically significant bradycardia- resting heart rate <45 beats/minute); tachyarrhythmia; clinically significant arrhythmias; presence of an accessory bypass tract (e.g. Wolff-Parkinson-White syndrome); unstable angina pectoris; current or prior history of heart failure or known left ventricular ejection fraction ≤40%. In addition; smoking of 10 cigarettes or more; diabetes; co-existent conditions which could independently affect resistance vessels (e.g. any disease which may be associated with vasculitis: collagen-vascular diseases, chronic hepatitis B antigenemia, circulating immune complexes, complement disorders, amyloidosis, scleroderma, etc.); other concurrent severe disease which could preclude participation or survival, such as neoplasms or Acquired Immunodeficiency Syndrome (AIDS), or patients known to be human immunodeficiency virus (HIV) positive; any known bleeding or platelet disorder; mentally or legally incapacitated patients; or inability or unwillingness on the part of the patient to sign the Patient Informed Consent Form. ]]> The study protocol was approved by the Human Research Ethics Review Committee of the Jewish General Hospital, where the study was carried out. A cohort of 15 normotensive subjects (NTN), 16 patients with hypertension (HTN), 15 HTN with metabolic syndrome (MetS) and 16 HTN with chronic kidney disease (CKD) were recruited from June 25, 2013 to April 25, 2016 according to the criteria of inclusion and exclusion described above.]]>