8 research outputs found
Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone
Get PDFAging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging
In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome
No full textMetabolic syndrome is a significant worldwide public health challenge and is inextricably
linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential
cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the
unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition
of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial
fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the
novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated
renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic
syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of
pro-fibrotic markers (Col1a1, Col3a1, Col4a1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in
UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of
intercellular adhesion molecule 1 (ICAM-1) and -smooth muscle actin (-SMA) were diminished in
SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+
and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated
in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might
be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in
hypertension and metabolic syndrome
In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome
No full textMetabolic syndrome is a significant worldwide public health challenge and is inextricably
linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential
cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the
unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition
of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial
fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the
novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated
renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic
syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of
pro-fibrotic markers (Col1a1, Col3a1, Col4a1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in
UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of
intercellular adhesion molecule 1 (ICAM-1) and -smooth muscle actin (-SMA) were diminished in
SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+
and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated
in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might
be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in
hypertension and metabolic syndrome
