Papers by Srikanth Givvimani
Hypertension, 2012
Activation of renin-angiotensin system and production of Angiotensin-II plays an important role i... more Activation of renin-angiotensin system and production of Angiotensin-II plays an important role in several pathological processes leading to end stage renal disease. Sustained hypertension induces renovascular remodeling in both intra and extra-renal vasculature by altering extracellular matrix (ECM) components. Recent studies in vascular remodeling have shown strain-dependent phenotypic variation in carotid artery and in pulmonary hypertension indicating a genetic basis for disease susceptibility. We hypothesized that sensitivity to develop hypertension to angiotensin-II infusion and subsequent renovascular remodeling will vary depending on the genetic background. C57BL/6J (WT) and TIMP2 -/- mice were used in this study. Osmotic pumps loaded with Angiotensin-II (Ang-II) were introduced into a dorsal subcutaneous pocket for delivery at 250 ng. kg -1 . min -1 . Pumps loaded with saline served as controls for both groups. Blood pressure, renal vascular blood flow, renal vascular densi...
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Hypertension, 2014
Ageing is associated with structural and functional changes in the kidney and the presence of hyp... more Ageing is associated with structural and functional changes in the kidney and the presence of hypertension in this population further contributes to renal complications leading to renovascular sclerosis. Emerging evidence suggests that hydrogen sulfide (H 2 S) pathway participates in the pathogenesis of hypertension. Furthermore, chronic inflammation is known to play a critical role in ageing and development of hypertension. In this study, we hypothesized that angiotensin-II (Ang-II)-induced hypertension causes renal fibrosis by sustained activation of pro-inflammatory M1 macrophage promoting the release of inflammatory cytokines and treatment with H 2 S attenuates renal injury and fibrosis by promoting alternate activation of anti-inflammatory M2 macrophage. C57BL/6J (wild type, WT) mice, aged 18 months, were infused with Ang-II (1000ng/Kg/min) or saline using osmotic pumps for 4 weeks and treated without or with H 2 S in drinking water (30μM/L). Animal groups were 1) Saline, 2) Sa...
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The FASEB Journal, 2011
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The FASEB Journal, 2013
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The FASEB Journal, 2011
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The FASEB Journal, 2012
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The FASEB Journal, 2012
Hypertension is a recognized cause of chronic kidney disease and end‐stage renal dysfunction. Sus... more Hypertension is a recognized cause of chronic kidney disease and end‐stage renal dysfunction. Sustained hypertension induces renovascular remodeling in both intra and extra‐renal vasculature and alters extracellular matrix (ECM) components. Our objective was to define renovascular phenotypes in agonist induced hypertension in different strains of mice. Osmotic pumps loaded with Angiotensin‐II (Ang‐II) were inserted subcutaneously into C57BL/6J (WT), TIMP2−/−, and C3H/HeJ mice for delivery at 250 ng. kg‐1. min‐1.ResultsAng‐II induced higher blood pressures in WT and TIMP2−/− mice compared to C3H mice. Blood flow across renal artery and aorta was decreased by 33% in TIMP2−/− mice; whereas, in WT and C3H mice, flow decreased by 23 and 20% (aorta) and 19 and 10% (renal artery) compared to untreated controls. Barium microangiography showed decreased renal vascular density in TIMP2−/− and WT groups than in C3H. Peri‐glomerular and vascular collagen deposition was increased in TIMP2−/− and...
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Circulation, 2014
Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for various cardiovascular ... more Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for various cardiovascular diseases including hypertension, coronary artery disease and atherosclerosis. Previous studies have reported the anti-atherogenic properties of paraoxynase1 (PON1) through its homocysteine thiolactonase activity. Studies from our lab have shown abnormal matrix remodeling due to elevated MMP-9 expression, decreased vascular connexins (37 & 40) and endothelial dysfunction during HHcy. In the current study we examine the role of homocysteine and its effect on vascular remodeling during atherosclerosis in PON1 knockout mice. We hypothesize that PON1 knockout mice develop HHcy that induces MMP-9 expression and causes decreased Akt/ eNOS expression leading to vascular remodeling in atherosclerosis. Methods: PON1 knockout mice were fed on atherogenic diet for 15 weeks as atherosclerosis disease model and compared with C57BL/6J (wild type) controls. Blood pressure was measured by tail cuff metho...
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The FASEB Journal, 2012
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Pharmacology, 2013
Background: Vasomotor responses conducted from terminal arterioles to proximal vessels may contri... more Background: Vasomotor responses conducted from terminal arterioles to proximal vessels may contribute to match tissue demands and blood supply during skeletal muscle contraction. Conduction of vasodilatation (CVD) from distal resistance arterioles to the proximal arterioles and feeding arteries during metabolic demand is mediated by intercellular gap junctions in the vascular endothelium. The role of hyperhomocysteinemia (HHcy) in the musculoskeletal system during CVD is unclear. We hypothesize that during HHcy, there is impaired CVD due to decreased expression of endothelial-associated connexins and thus decreased tissue perfusion to the contracting skeletal muscles. Methods: CVD studies were performed in a gluteus maximus muscle preparation of wild-type (C57BL6/J) and CBS-/+ (HHcy) mice using intravital microscopy. Expression of connexins and myostatin protein (an antiskeletal muscle statin) was studied by Western blot and immunohistochemistry methods. Tissue perfusion to acetylch...
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Archives of Physiology and Biochemistry, 2010
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The FASEB Journal, 2010
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The FASEB Journal, 2012
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Journal of Receptors and Signal Transduction, 2010
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The FASEB Journal, 2015
Previously, we reported aberrant mitophagy contributed to cardiac failure and inhibition of mitoc... more Previously, we reported aberrant mitophagy contributed to cardiac failure and inhibition of mitochondrial fission was cardioprotective. Cardiac connexins (Cxs), play crucial role in ischemic preconditioning, myocyte coupling, and serve to regulate post ischemic cardiac dysfunction and apoptosis. Diabetic cardiomyopathy is associated with abnormal mitophagy and decreased Cxs expression. Although moderate exercise is reported to be beneficial in cardiovascular diseases, it is not known whether exercise can mitigate aberrant mitophagy and induce Cxs in diabetic cardiomyopathy. We hypothesize that exercise decreases the aberrant mitochondrial fragmentation (mitophagy), increases Cx-37, -43 expression and attenuates cardiovascular dysfunction in diabetes. To verify our hypothesis, we used db/db obese type 2 diabetic and control mice. Mice underwent 8 wks of moderate exercise on treadmill. Blood pressure (BP) by tail cuff method showed decreased mean BP and echocardiography demonstrated improved left ventricula...
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International Journal of Biomedical Science, 2014
Parstatin, a novel protease activated receptor-1 (PAR-1) derived peptide is a potent inhibitor of... more Parstatin, a novel protease activated receptor-1 (PAR-1) derived peptide is a potent inhibitor of angiogenesis. We and others have reported that imbalance between angiogenic growth factors and anti-angiogenic factors results in transition from compensatory cardiac hypertrophy to heart failure in a pressure overload condition. Though cardio protective role of parstatin was shown previously in ischemic cardiac injury, its role in pressure overload cardiac injury is yet to unveil. We hypothesize that supplementing anti-parstatin antibody during pressure overload condition augments angiogenesis and ameliorate left ventricular dysfunction and heart failure. To verify this, we created ascending aortic banding in mice to mimic pressure overload condition and then treated mice with anti-parstatin antibody. Left ventricular function was assessed by echocardiography and pressure-volume loop study. Angiogenic growth factors and anti-angiogenic factors along with MMP-2,-9 were evaluated by west...
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Stroke, 2012
Hyperhomocysteinmia (HHcy) is associated with neurological disorders (Stroke, Alzheimer, Parkinso... more Hyperhomocysteinmia (HHcy) is associated with neurological disorders (Stroke, Alzheimer, Parkinson etc) and causes blood brain barrier (BBB) dysfunction. We previously showed that an elevated level...
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The FASEB Journal, 2014
Advanced age and hypertension are risk factors for chronic kidney disease. Emerging evidence sugg... more Advanced age and hypertension are risk factors for chronic kidney disease. Emerging evidence suggests endothelial-mesenchymal transition (EndoMT) as a possible source of renal myofibroblasts which ...
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International journal of physiology, pathophysiology and pharmacology, 2011
Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) is associated with car... more Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) is associated with cardiac arrhythmia and sudden cardiac death (SCD). Hcy increases iNOS, activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) interupt cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling. We hypothesize that Hcy increases mtNOS, metalloproteinase activity, disrupts connexin-43, exacerbates endothelial-myocyte uncoupling, and induces cardiac failure by activating NMDA-R1 in structural heart disease. Chronic volume overload heart failure was created by aorta-venacava (AV) fistula. HHcy was induced by adminstrering Hcy in drinking water. NMDA-R1 was blocked by dizocilpine (MK-801). EKG and M-mode Echocardiography was performed. The E-M coupling was determined in cardiac rings. LV mitochondria was isolated. Levels of NMDA-R1, pero...
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Papers by Srikanth Givvimani